Lifelong endocrine fluctuations and related cognitive disorders.

50
HAL Id: inserm-00243083 http://www.hal.inserm.fr/inserm-00243083 Submitted on 13 Nov 2009 HAL is a multi-disciplinary open access archive for the deposit and dissemination of sci- entific research documents, whether they are pub- lished or not. The documents may come from teaching and research institutions in France or abroad, or from public or private research centers. L’archive ouverte pluridisciplinaire HAL, est destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d’enseignement et de recherche français ou étrangers, des laboratoires publics ou privés. Lifelong endocrine fluctuations and related cognitive disorders. Marie-Laure Ancelin, Karen Ritchie To cite this version: Marie-Laure Ancelin, Karen Ritchie. Lifelong endocrine fluctuations and related cognitive disorders.. Current Pharmaceutical Design, Bentham Science Publishers, 2005, 11 (32), pp.4229-52. <inserm- 00243083>

Transcript of Lifelong endocrine fluctuations and related cognitive disorders.

HAL Id: inserm-00243083http://www.hal.inserm.fr/inserm-00243083

Submitted on 13 Nov 2009

HAL is a multi-disciplinary open accessarchive for the deposit and dissemination of sci-entific research documents, whether they are pub-lished or not. The documents may come fromteaching and research institutions in France orabroad, or from public or private research centers.

L’archive ouverte pluridisciplinaire HAL, estdestinée au dépôt et à la diffusion de documentsscientifiques de niveau recherche, publiés ou non,émanant des établissements d’enseignement et derecherche français ou étrangers, des laboratoirespublics ou privés.

Lifelong endocrine fluctuations and related cognitivedisorders.

Marie-Laure Ancelin, Karen Ritchie

To cite this version:Marie-Laure Ancelin, Karen Ritchie. Lifelong endocrine fluctuations and related cognitive disorders..Current Pharmaceutical Design, Bentham Science Publishers, 2005, 11 (32), pp.4229-52. <inserm-00243083>

����������� ������ ��������������� ������������� ��� �� ������� ����� �������������!��"���#�$��������� �

� %'&)(+*�,.-�(�/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/32��45&)( 6.7��%$%$*98;:94<,=(>456.?9&@/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/3A�B?=(+*=6.C'D=-�(;436.?E/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/3F�HG)I�8J-;K�,�?945&#LM&�6.7�N=6.?�,�C�,9O�K�6.*9L�6.?P8Q8;7>7R8J-�($&�6P?S-'6TN.?945(>436.?�/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/3FU9VXW$Y[Z]\3W^VJ_;`'\�a�b;c`Rad\BVJb�_;`RZW�eJ\�Yfb^ZQg1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g3hi j�Ylk�`RZ�ed`�cdVJb>mn_R`;Z;`'\BY3e�a@\poXk9Yl`;aJg1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g3qr \B`>Vsb^Ytk�`>cdcd`JeJ\�a�b$Z�Z;`9odVJb9\BVXWuZ$a5mQY5\v\B`>V�adw�ad\B`@mQa$g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g5xy \Bz�`>V Z;`.oXVsbR{dVJb9\|`JeJ\�Y�j|`E`+cXcd`JeJ\}a�b;c`Rad\BVJb�_;`RZ$a;g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g3~���HG���6.*PL�6.?�,9OQ8;�'�$6=&�D'*98Q,=-u*P6�&)&�(+K�8 O$4<7R8$�5&}�;,�?�,s?'C]8;7>7;8J-'($&�6.?]-�6=N.?�45(;4<:P8�7>D�?=-�(;4�6.?94<?PN�/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/3��'`�\5W;��`@�${$b$a>odV>`EWuZ;kM`+cXcd`JeJ\}a�b$Z�Z;`9odVXW^��bRVs_pWuZ$Y[��W9\�Y<b$ZQg0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g3��Eod�>`+V'\@wsW$Z;k�W;koX�$\sk�`=jB`>�;bR{@m�`RZ9\$W$Z;k�b;�>a�`+V=jB`>k�a�`@��k9YlcdcX`+V>`RZ�ed`RaTY[Z�e$b�_$Z$Y�\}Y�jB`c�o>Z�eJ\�Y3b$Z$Y[Z�_�g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g��)���`RZ�b;{@WTo>a�`EWuZ;k�e$b�_$Z$Y5\BY�j|`�c�opZ�eJ\}Y3b$Z$Y[Z�_g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g��#�� _;`RY[Z�_��lV>`>�vW9\B`>k�e$b�_$ZRY�\�YBjB`�k�Y[a@b;V>k�`>V�W$Z;k�k�`@m�`RZ9\BY0W�g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g��#�`RZ;k�b'edV;Y[Z;`�cd�Jo$eJ\do@W9\}Y3b$Z$aJW$Z;k�e$b'_$Z$Y5\BY}jB`�c�o>Z�eJ\�Y3b$Z;Y[ZJ_T�HW�e$b$Z9\BY[ZTo�o@m�m�b;k'`+��g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g��#h�����HG��T�=6=NT8;?=6.DP&.K�6.*9L�6.?�,POQ8;7>7R8J-�(;6.*=&T,�?�C�-�6=N.?�4�(;456.?Q/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/��#�\Bz�`]�9b;V>�@k��}�JYlk�`�k9Y�jB`>VRa}Y5\@wTb;c� Q¡E¢�g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g��#qi9c>cd`JeJ\�b;c� Q¡E¢�b$Z�Z�bRV@mW;��e$b�_$Z$Y5\BY�jB`c�o>Z�eJ\�Y3b$Z$Y[Z�_�g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g��vx Q¡E¢�WuZ;k�k�`Xm`;Z9\�Y0W�g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g��#���£�¤v¥@¤#¦$§l¨l¥@¤¤0©[©d¤vª@§;«d¦ ��¬0­#® ¤v¨[¯�¤v£�° ±�²>¨l±H¤#³>±H¤d�$«>´p±H¤v£B¥v³^§l¨µ«d¦ ±H§l¶p²R¨[¤#±$·0·1·0·0·1·0·1·0·0·1·0·1·0·0·1·0·1·0·0·1·0·1·0·0·1·0·1·0·0·1·0·1·0·0·1·0·1·0·0·1·0·1·0·0·1·0·1·0·0·1·0·1·0·0·1·0·1·0·0·1·0·1·0·0·1·0·1·0·0·1·0·1·0·0·1·0·1·0· ��¸��£�¤v¥@¤#¦$§l¨l¥@¤¤0©[©d¤vª@§;«d¦ ��¬0­#® ¤v¨[¯�¤v£�° ±�²>¨l±H¤#³>±H¤d�J¢ ® ¤�±t¹º¤vªv¨ ©d¨[ªv¨»§1¨[¤#±�«<© § ® ¤�¼� Q½[� r ¡E¾�¢.·0·1·0·1·0·0·1·0·1·0·0·1·0·1·0·0·1·0·1·0·0·1·0·1·0·0·1·0·1·0·0·1·0·1·0·0·1·0·1·0·0·1·0·1·0·0·1·0·1·0·l¿@ÀiX©[©p¤vª@§;«»©= �¡E¢�«d¦�§ ® ¤�±H¤#¥@¤v£�¨»§ Á�«»© ��¬0­�® ¤v¨[¯�¤v£�° ±�²>¨l±#¤#³>±H¤T·0·1·0·0·1·0·1·0·0·1·0·1·0·0·1·0·1·0·0·1·0·1·0·0·1·0·1·0·0·1·0·1·0·0·1·0·1·0·0·1·0·1·0·0·1·0·1·0·0·1·0·1·0·0·1·0·1·0·0·1·0·1·0·0·1·0·1·0·0·1·0·1·0·0·1·0·1·0·0·1·0·1·0·0·1·0·1·0·0·1·0·1·0·l¿@¿aX\poXk�wP�@Y0m�Y5\�W9\BY3b$Z$aJW$Z;k�j5W+VRY1W;�>Yl�XY3\@wsW;a�\Bz�`�{dVRY[Z�e>Yt{�W^� evWTo>a�`�b;c�Y[Z�e$b$Z$a�Y[ad\B`;Z�eXYl`;a9Y[Z�V>`Ra+oX�R\}aJg1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g5�)�i^¹T¨t²R¤v¯�¨[« ¬ «@Â$¨[ª#³ ¬ ±�§l¶p²p¨µ¤#±�³>¦>²�ªv«@Â;¦R¨»§t¨l¥@¤¤#¥v³ ¬ ¶d³^§1¨[«p¦J·0·1·0·0·1·0·1·0·0·1·0·1·0·0·1·0·1·0·0·1·0·1·0·0·1·0·1·0·0·1·0·1·0·0·1·0·1·0·0·1·0·1·0·0·1·0·1·0·0·1·0·1·0·0·1·0·1·0·0·1·0·1·0·0·1·0·1·0·0·1·0·1·0·0·1·0·1·0·0·1·0·1·0·0·1·0·1·0·0·1·0·1·0·0·1·0·1·0·l¿XÃ��¤#¦R«B¹.³R¶d±H¤#Ä@ Q¡E¢�©d«+£�¯�¶ ¬ ³^§l¨µ«d¦d±�³>¦>²�´>¨[« ¬ «@Â$¨µª#³ ¬ «+¶>ªv«>¯�¤#±d·0·1·0·0·1·0·1·0·0·1·0·1·0·0·1·0·1·0·0·1·0·1·0·0·1·0·1·0·0·1·0·1·0·0·1·0·1·0·0·1·0·1·0·0·1·0·1·0·0·1·0·1·0·0·1·0·1·0·0·1·0·1·0·0·1·0·1·0·0·1·0·1·0·0·1·0·1·0·0·1·0·1·0·0·1·0·1·0·l¿@Åi9c>cd`JeJ\�a�b;c�bP\|z�`>V�`Rad\BVJb�_;`RZ;Y3e�m�b;kod��W9\�b;Vpa�b$Z�e$b�_$Z;Y5\�Y�j|`Ek9Yla)bRV+k'`+VRaJg1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g5�dx��! G)ÆsKºÇT&#456TO^6TNT45-u,PO�L�,�*9È�8;*.&.,=&)&v6�-J4<,=(;8;C�É�45(pKÊO;4»7;8$O^6.?9N�-uD'L�D9O;,=(;4<:98 8J&)(+*=6=NT8;?�8>���^6�&�D'*98�/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/52)Ër `>V9o@m"z�b;VXm�b$Z>W;���@`Tj5`+�XaJW$Z;k�_;`RZ;k�`>Vk9Ylcdcd`>V>`RZ�ed`Rasg0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g5�)~r `>V9o@m"z�b;VXm�b$Z>W;���@`Tj5`+�XaJW$Z;k�e$b�_$ZRY�\�Y�jB`k9Yla@b;V>k�`>V;a>g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g5�)��'z�w}aHY3b;�;b'_$Y3e@W^�=mEW^VRÌ;`>V>a'W;a#a@b�e>Y0W.\�`>k"�JY5\Bz��@Ylcd`>�;b^Z�_Q`>ad\BVJb�_;`RZQcd�Jo$eJ\do@W9\}Y3b$Z�g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g0g1g0g1g0g5�+�! G@��6�ÉÍ,'*�C=&T,�?�4<?.(;8$N.*�,=(;4<:P8QL�6.C98$O 6.7�-uD'L�D9O;,.(;4µ:98�8J&@(+*=6TNT8;?M8+�'�$6�&#D�*98$/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/5A)A��6.?=-sO;D.&�4�6.?�,�?�C�7>D=(+D�*98QC'4<*98J-�(;4�6.?=&./0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/5A)���8$7;8;*P8;?=-s8J&$/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/0/1/0/1/0/5A)Ë

HA

L author manuscript inserm

-00243083, version 1

HAL author manuscriptCurrent Pharmaceutical Design 2005;11(32):4229-52

¿

���������E��Q� ���� ��������������Q������������� ��� �� ������������� �������������!�� ���H�$��������� �

I G1�EG)�Q ������} ����� Gd���H���������

������ ������������������� �����!� "$# "&%�')(*�+�-,.# �/�0�21*(3#545�67�8(9 :1�;-�/�=<>�� :?+"3@ACB�'ED�����FG(�D�;�"�# "&%�2�6��IHKJ9��LDE(3#5MN(O,�"&# "0�!P� Q� R�6�

FG(S?0�T# #2"&�VU$W��$X�(S?0���&@A�Y,Z;0(9 :# �*\[G#T(S;0(S@#LD:�$].F^�0U�UX����$�&U���X��`_a"9�3D��A�8#2# � �� b,.�*���7ced��$[A E(*��13�

fb��#:g&���K�`UKX�Xh���.Udh�$�+ij[A(Sckg&���h�`UKX�X`���.U�dKl�X$i�_m(3�T#Eg&(*��1*�*# �T�no�!"0�SDp�kq �T���� ��^q rE

� %'&)(+*�,.-�(

fN;��`(3�T�s"&rNDE;�� 5 R��?�� ��t�� .D�"u��c+(3�!�/��YDp;�K :�*#T(8Dv� "&��;�w�CP�xDvth�*���m�����"&1* :�/��hr�#w@1�D�@(�DE� "&�u(*�+�e19"&%���LDE�/?�hr�@+�1�DE�2"&��T��%Gq$y

�# �RDE;+"j �(h"&r9¨t¦�¥@¨»§l£}«K(*����¨l¦�¥@¨t¥@«eED�@+�j�2�6I;�(*?�z�����!"&�{EDv :(8D��*��Dv;�5��7@ �"3�+ :"*D:�*1�Dv�T?�5 :"�#2��"&rb�*EDE �"&%���.(S���D�;�*�T \�T�K�(31�D|"&�

D�;�}���@+ x"*DE �(*���!�LD D��8 ��'ED����!`�T�K�{#T� 1*(�DE�*�C�T�~13"0%���LDE� "&�Gq�4���13���3D�;"& ��!"&��(3#N R�7�{#T(913���!���3DbDv;�� :(S��'��2Hh4�fb�\DE :�T(3# z�T�C�"&��

�����!���jD��*�O�A"0vD:���!���"9�(S@{R(9#�th"0�!�����@+%�%�*ED!(mDE���K�+"j R(9 E')�"�R�LDE�/?�a�*rEr��*1�De�p�"*DE(*P#w'�"&��?�8 vP(3#z�!���!"& �'0�:��(*���rE"9@

:��13���3DI�!��DE(j��(S�0(9#w'$7�*�19"&��?�� E%�5D�"^x@%�%+�6EDI(K�"��R�wPA# �z�{ �"6Dv�*1�DE�T?�K�*rEr��*1�D.�T�u R�8#T(8Dv� "&�!D:"^yh#T�*;�*�T�!�� 8� z��� 7�8(&��K�� :�*�&@+1*�T��%

:� ��KP+'!WX`DE"!U$U����q9HK"&th��?�� x�+�&(8Dv(hrE �"&��D�;�`"&��#T'�#�(9 E%�z :(*����"0�!���9�*�!19"&�3DE :"�#2# �*��DE :�T(9#+��@�PA# � �;�*�hD�"!�&(�DE�6�&Dv;����"&�!���{�

Hh��(j#LD�;��E�+� Dv��(�DE�T?�o_O���!"j �'�BjD�@+�3'�z��� ���"*D�1*"&��r��� ���D�;�*��O"9P{7�8 v?0(�DE� "&�C(S��);�(9?�O��?�����@�%�%+�6ED��*��(*���T��1* R�8(&R�O�T�

�����!���jD��T(� :� ���rE"& �t`"&�!����@{R�/��%sHh4�f�1*"&�`�(3 ��*��Dv"�19"&�3DE :"&# *qoB��?+�8 �(3#O�!�RDE;+"���"&# "&%�T1*(9#)���TrEr:�� R���019�3�PA�xD�t`�*�*�

"9P{��� E?�(�DE� "&�uED�@���2�6�(*�+�!13"0�SDv :"�# #2�*�hDE ���(9# �t�� Dv;e ���%�(3 :�`D:">�(�DE�T���3D\%� :"9@��{�$D�'&�{�*��DE�/�!�T��%e(S����9@ :(�DE�T"&�u"jr|Hh4�fZ��1*"3%$��LDE�T?�

�!�8(&�@ R�*\(*���h(S��(3#T'7�6��$(3 ������ R1�@A���*�5DE"K�7c��A#�(9�T��D�;�*��5��� R1* R�7�(*��13�2�6*q9f|;0��(j��"j19�T(8DE� "0�hPA�xDpth�*���!;"& v�!"&��(3#A��� E@+��# ��?�*#

(*���m13"0%j�+� D��T?�>r�@��1�D�� "&���T��%m R���V(&�T�`19"&�3DE :"&?+�8 RR�T(3#.�@%$%�6vD:�T�&%o;0�/%�;a�T�3D:�� x���/����T?�� �9@(9#\?j@A#T��� :(SP�T# �LDE'a�/�� ��/x��q�_O"& :�*"&?�� x�

:�*���(3 �1�;~"&�eDv;�>�T�h�+(31�D�"�r5�����"&1* :�T�+�Kr�@��1�D�� "&���T��%m"&�~19"&%����LD:� "0���9@ ����$%eDE;+�Kr:���K(j#2�K x�7� �"��9@1�D:�/?�K1*'�13#2�!�@%$%�6vDxz#T��r��3�

# "&�&%mrE#�@A1�D�@(�DE�T"&���/�~?&@#T�+�8 �(*P� #T�LDv'�q��GDE� "&# "&%+��1*(9#N�!"$���*#��DE(*���T��%C�T�3D:"u(91*13"9@��3D\DE;�>�w�SD��� :(31�Dv� "&�m"jr�13#T�T��T1*(9#/�� :�7� :"��9@A1�DE�T?�*�

(*���`�!���{EDv E@(9#A��?���3D:�Dv;� :"9@+%�;"9@jD�# �Tr:���V(9'`� :"&?+� ����(z�!"� ���?�(9#��2�K(*��� �"&(31�;K�T�h@+����� xvDE(*��&�T�$%�Dv;�5�*rEr:�*1�D:I"&r�vD:�� :"��2�0I"&�

D�;�`P �(3�w�~(S��~�w�m���RD:�� ��!�T��T��%m�@�P{�2%� R"9@��{z(8DI;0�*�/%�;3D:����*�C :� ��GqG,I"9%���LDE�T?�>��� �"& ����8 R��/�eD�;���*# ���� :#/'~(3 ��K�!"& R�K# �T��*#T'�P{�

:��#T(8D��*��DE" 1�@+�`@{#T(8Dv�*� # �Tr:�*# "&�$%���c��A"��@ R�-Dv"�ED��� :"�� ����� :(�Dp;�8 oD�;�(*��D:"¡(����*1*�2rE� 1��7c��{"��@+ :�-D�"¡(�%�T?����ED��8 R"&� �Aq

_m@#LDE�TrE(91�DE"& :�T(&#\�!"����*# zP(j7�*�m"9�a(*�a�7c;�(S@{EDE�T?+�!?+� ��t�"�r5(3#T#\;"& ��!"&��(3#.��?���3D:5Dv;� :"9@+%�;"9@jD5 :�7� �"��9@1�D:�/?��# �Tr:�KDE"&%�RDv;�8

th�LD�;e"*D�;+�8 \ :� ��!rE(91�DE"& x.���+"6Dv(*P#T'K%+����xD��T1� :� ��!rE(91�DE"& x\ R��#�(*DE�*�5D�"!�*EDE :"9%���! R��13�7�jD�"j ��{"&#T'��!"& v�;� ��}��b�;"9@A# ��PA���7c��A# "& :�*�

DE"`1*#�(9 :�TrE'�D�;�� :"&# �5"&r�;"& ��!"9�0(&#+ :� ��KrE(31�DE"& R���"& �� �"6Dv�81�DE�/?��rE(91�DE"& x\rE"& N1*"&%��+� Dv�T?�5�&'Rr�@+�01�Dv� "&�K(*��`�����e���3D��T(q

�!¢�£¥¤V¦�§*¨A©*ª 19"&%&��LD:�2"&��«yh#T�*;�*�T�!�� 8� ¬��� 7�8(&R�*���*EDE :"0%������r:���K(&# �s :�7� :"��9@A1�DE�T?�s1S'1*# �*���!���"&�+(*@{R�*�«;"& E�!"0�{�

:�7�#T(319���!���jDAD�;�� :(S��'��1�@+�h@+#�(�D:�*�`#T� r:�*#2"&��%K��c��A"��@ ��bD�"VEDv�8 R"&� ��*q

HA

L author manuscript inserm

-00243083, version 1

Ã

��45&)( 6.7��%$%$*98;:94<,=(>456.?9&

y��egSyh# ��;�*�/�e�� 8� \��� 7�8(&��y�_aFAy�g3(9�K�T�"K�z;�'�& :"9c+'}dz�!�RDE;$'# � R"9c(3�9"�# ��U`� :"9��T"&�(�DE�y5�{"&�5g3(S�"&# �w�{"9� �"6D����T�V�y�FGFbg9(*�K'+# "��T���+ :�*1�@ RR"& �� :"*DE���T�y

β:(*�`'# "�� �

β]���<K[\g*P �(3�w�K���8 ��T?�*�`��7@ �"6Dv :"9�;+��15rE(91�DE"& ]._��!gSP"&�+���!�/��8 �(3#+�����{R�LDv',.�N��g31*"&���:@$%0(�D:�*�K���9@{�/��5�6EDv :"&%���,N<�B�g31*���3DE �(3#$��� E?"9@{.�'ED����,."���Bf|y�4hg&ED�@�9'!"&rADE(*�!"9cA�Tr:���K(*��` :(9#�"9c�Tr����G19"&%���LDE�2"&�,.4��N]�g31�y�_oFu :�*��"&�7�T?�*�E�*# �������3D�P�T����/��%h�+ :"*DE�*�T�,.4�Fbg3,o :��(31�Dv��?+�.� �"6D��*�T��5yeg9��"9�(9�!�T�����.B�g3�&� �RDE;$'# EDE� #wPA�6EDv :"�#�N4hg9�*EDE :"0%���V ��819���jDE"& �N4�f5g9�6EDv :"9%���K :�7�{#T(319���!���3DAD�;�� :(*�$'[NB$Heg3rE"&# #2��19# �YvDE�T�`@{#T(8Dv�T��%`;"& :�!"0��6� yh]Iyeg

�(*�!�/�"9P�@jD�'� :�T15(31*�2�

� ��4.Heg9%+"&��(3��"*DE �"3�+�T�V ��*# ��(jR�T�$%h;"& ��!"&��H���M�gS;�T%$;V�����7�LDE'K# �w�"9� R"*D:���T�Hh4hgS;�(3�*(9 :�` E(8DE�T"Hh4�f5gS;0"& ��K"&��� R�7�#T(319���!���jDAD�;�� :(S��'M ��M�g9# "&t������7� Dv'K# �w�{"9� �"6D����T�M�Heg9#w@jD:�*�/�0�2�*�T��%K;"& E�!"0��6_my��>g9�!"&�"&(*�!�T�+�Y"9c�2�j(&��_my�F��>g9�!� D�"&%���K(31�Dv��?�(�D:�*�z� :"*DE�*�/�h��/�0(&R����K�E_a_«B��g&���!"��$��r�� �*�&���!�T�� �p�!���jDE(3#AEDE(�D�@{|��c+(*�!�T��(8Dv� "&�_aF�y}g9�!�*�& R"9c�'&� R"9%�3ED��8 �"&���(913�RDE(8Dv�<`yegS�"& :(9�j �����(3# �T�+�< � [\g*��� E?+��%� �"&t�DE;KrE(31�DE"& <K_���yeg8<>���!�RDE;�'+#/���`��(j��(9 �D�(8Dv���,�g9"& :(9#1*"&�3DE �(31*�7�jDE�T?+��54hg9"����` :(�Dv��"FG��f5g*�"�R�LDE �"&�!���!� �R� "0��DE"0�!"&%� :(*�$;�'FG�:���>g*��;+"0x��;�(8DE� �0'#T�T�"���LDE"$#{���p���T��(j7�FG4��NFAy�4���g*� ���?+���SD��w��%`�{"�EDv�!���"&(*��@AR(3#$�!���!"& :'K# "��\(S���y`#��S;�*�T�!�* �� \��� ���(j7�.th�LD�;K R���+#�(913���!���jD|�6vDE :"9%���4Y,\f5g3 E(S����"&�!�T�3�*�`13"&�3DE �"�# # �*�5DE ���(9#B�N4�_-g&R��# �*1�DE�T?�5�*EDE �"&%���K :��13���jDE"& |�!"&�3@A#T(8DE"& BF��b,\fYg&R�w�&%# �I��;"*D:"0�!���!�/7��T"&�K13"&�K�$@jD:���5D:"&�!"0%0 �(*��;&'��Hh�:��_o�RBkg9th"&�!����� |;�8(9#LDE;K�T��LDE�T(8Dv�T?�Y�p�!�*�!"& �'���vD�@�&'���RB����5_-gSth"&�!���k� \�/�SD��� E��(8DE�2"&��(3#AED�@�&'K"�r�# "&�&%!�9@ �(8DE�T"&�K"��*EDE :"0%���V(9r D:�� ��!���"9�(S@{7�d��2Hhf5gj��8 �"6Dv"&��T�

HA

L author manuscript inserm

-00243083, version 1

Å

�B?=(+*=6.C'D=-�(;436.?

f|;0�u7�T%���� rE� 1*(S�3DE#T'a;+�T%�;�� ��+ :��?�(3# ���+13�u"&rzyh#T�*;�*�T�!�� *� K��� 7�8(&R�~�py �z�h�T�m�A"�ED:�p�!���"9�(*@{�(3#\th"&�!���)"9P{7�8 v?�*�a�2�

�!"�ED|th�6vD:�� ��!13"9@�3DE �� �*\;�(jI# �*��D:">�w�1* :��(jR�/��%e�T�3D��8 ��6vDb�w�KD�;�5 :"�#2��"&rN%"0�0(9�&(3#A;+"j ��!"&�+�6��+(S���!�T�K�(9 �DE�T1�@#T(9 b�*EDE �"3%+���$�+�2�

1*"&%���LDE�/?��r�@+�1�DE� "&�+�T�&%�q � �T?���KDE;�(�Db�*EDE �"9%���e R��13���jDE"& R�(9 E�h�7cjD������T?+�*#T'!� ��67���3D\�T�!P �(3�w�VDv�/7�@{�*�A(`t�"& :#2�0�pth� ���`���7P{(�DE���

1�@ : ����3DE#/'m@��$�8 �t�(*'a19"&��13�� E��T�$%~D�;�>�{"*D����3D:�T(3#\?�(9#�@A�u"�rz;"& E�!"0�0(9#. R���#T(913���!���jD�D�;�� :(*�$' �2Hh4�f\���w�a R�8�9@A1*�T��%a(*%+�*�T��%�

:��#T(8D��*�!13"0%���LDE�T?�`1*;�(S��%�*��A(S������*#T(*'�T�$%$��� r\�"*D|� :��?+���SD��T��%�$D�;�`"&���RD."�r.�����!���&DE�T(q�4��*13���3D\r:�T�+�j�/��%�rE R"&��DE;�`# (9 E%��6vD

DE"!�&(�D:�� �(*����"&�!� 7�*�K�A#T(313�7P">13"&�3DE �"�# # �*�}Hh4�faD� ���(9#G�w��13#w@A���T�&%u"&?�� .U�T�����}t�"&�!���u;�(*?�`�@%$%�6vD:�*���+;+"&th��?�� x�$D�;�(8D�H`4.f

�V(9'u;�(S?�K(>;0(9 E�Kr�@{#|�*rEr:�*1�D�"&�~13�� R��P+ :"���?�(j�1�@#T(3 Yx'$vD:���e5(S���u13"&%$��LDE�T?�Kr�@+��1�D:� "9��/��%�G(S����K(9'���?���C�T�1* :��(j7�` :����C"�r

�����!���jD��T(q+fN;��*��KrE�/����T��%�;�(*?�Kr�"j �13�*�>@{.Dv"u :��?�2��t�� :��?+� "9@{���?+� ������13�Kr�"j �(K� �"*DE�*1�DE�T?�>�8r�r:��1�D.(9���!DE"u����?+�*# "&�m�!"& :�

:"9P�@{vD�����2�����!� "�# "0%�T1*(3#+�!"����*# \"�r� ��/x��q

���aDE;�� � ���?� ��t�th�C(3 v%&@{��DE;�(�D�D�;��C�!"ED!��8 �� "9@{u�;"& �D:��1*"&�!�T��%�"jr`�+ x��?�� "9@{�ED�@���2�6^;�(j>P�*���aD�;+�*�� >r:"&1�@{�"$�

;"& ��!"&��(3#51*;�(*�$%�6^(3r DE�� hD�;+�C�!���"&�(S@{R�*�.t`� Dv;"9@jD�Dv(*���T��%)�T�3D�" (91*13"9@��3D>���+���T?� �9@(9#5# �Tr:�3�TDE�T�!�o��c$�{"��@ ��eD�"o;"& E�!"&��(&#

?�(3 :�T(SP�T# �LD�'�A(*�+�VDp;0(�D\�K(3�$'^"&rNDv;�`�T��13"&�7�/vD:�7�13�2�6�r:"9@+��>P{�RDvth�*���~ED�@���2�6��K(9'�P{�`�9@{�5D:"`DE;+�hrE(91�DkDp;0(�D\th"&�!���C��">�"*D

(3 E ���?+�!(8D��!���"9�(*@A��>th�LDv;a� �3@+(3#. :� ��O"&r�13"9%���LD��w?�u���*1*# �/���"j `� �9@(3#.�@{�13���jDE�wPA� #T�LDE'uD:"�Dv;�u��rEr:�*1�D:}"jr�Hh4�f5q� �VDp;j@A

� :�*7���SD�(`�@��K�K(3 E'K"�r�1�@ � :�7�SD����"&t`# �*�&%��13"&��13�� ���w��%�DE;���!�*1S;0(9��� R�e\"$r{Dp;�����@+ :"9� R"*D:��1�DE�T?��(31�D��T"&�!"&rN�6vDE :"&%+���{\(*���

DE�T�!�T�$%!"jr�;"& :�!"0�0(9#A��c��"��@ R�\DE;� :"9@+%�;�"9@jDADE;+�Yr����V(&# �5# �Tr��3��1*'�13# �*�$(*��K�LD:|� �"9P(*P#2���8rEr��*1�DN"&�!1*"0%���LD:�w?�5r�@+��1�D:� "0�0�/��%Gq8���

D�;���K R��?0�2��t�ED�@A�j�2�6Z@��$�8 �DE(*�����hDE">�j(�DE�5"&��DE;�519"&%����LD:�T?+���8rEr��*1�D:."&rN�7cA"&%���"9@{Z;"& :�!"0�0(9#A�*rEr:�*1�D�"& x��0��"6Dv(*P#T'`Hh4�fZ�$(*���

rE�T��(3# #/'}�@$%�%�*ED�(*�K�w�SD���%� :(�DE�w?���!"����*#A"&r� :� ��`P(jR�*�K"0��D�;+�67��r��T����w��%�DE"`%&@� �$��r�@jD�@+ :�� ��67��(3 :1S;Gq

�HG)I�8J-;K�,�?945&#LM&�6.7�N=6.?�,�C�,9O�K�6.*9L�6.?P8Q8;7>7R8J-�($&�6P?S-'6TN.?945(>436.?

] ����� �������� ��������� ��������� �������������

y�131�@+�h@A#T(8DE�/��% ¨l¦ ¥@¨<§l£�«�(S�� ¨l¦ ¥@¨l¥@«���?� �$���13�O;�(&m�T��$��1*(�DE�*��7��?�� :(9#`�{"*D����SDv��(9#`P :(9�T�-DE(9 E%�RD:m"$r~�*EDE �"&%���*q

_a"&# �*1�@A#T(3 z�!�81S;0(9��� R�eV;�(3?+�!PA�*��� �7cjD������T?+�*#T'a :��?�2��th�*���R�8�E����(*��m1*(S�mP{�u�@+�K�K(3 :�2�3�*�m(j}rE"&# # "&th*q�f|t�"uDE'&�A�6>"&r

�6vDE :"&%+���e R�819���&D:"& x5���N4��N;�(S?�5PA�*���^�2�����3DE� rE� �*�u���N45�α

(S��!�|4Y�β

�|t�;�� 1S;e�!�*�$��(�DE�`���TrEr:�� x���3D\r�@+�01�D��T"&�*q�f|;�*��z :�*13���&DE"& x

(3 ��Y����19"����*�`P+'hDEth">�&� rEr:�� R���SD�%����3I# "&1*(8D��*�!"9�e��7�(9 :(8Dv�Y1�;� �"&�!"7"&�!�6ZP�@jD\�;�(3 :�/��%!13"&�K�!"0�^EDE v@1�D�@ E(9#ArE�8(�D�@ ��6��$t`� Dv;

D�;� :�*�z� :�/�019�w�(3#���"&�K(&�T���}Dv;�`(9�!���+"�TD:�� ��V�/�0(9#N"& \y p]���"0�V(&�w���Dv;����<Kyh�2PA�T����w��%~"& �,���"0�V(&�T�~�E�;"0th�T��%��!"& R�YD�;�(9�

X�d�� ;�"&�!"�# "&%$'uP{�RDvth�*���α

(*�+�β

�:��(*���!Dp;�!#T�T%�(9����2P�T��$�T�&%�"& 5�-�&"&�K(&�T���Ed�X$�s;"0�!"�# "&%�'���q+y¡r:"9@ �Dp;~��"&�K(&�T����[G���

�T��?�"�#T?+�*�u�T�~��� EDv�T��%&@{� �;��T��%�P{�RDvth�*�����*EDE �"&%���~(S%"&�� ED�5(*����(9�SDv(*%"9�� ED:SqM|�T��K"*DE;+�8 ��!���KPA�8 R�"&rNDv;�!ED��8 �"j�2�u :�*19���jDv"j

�@���� :rE(9�K� #T'�.�|4 (* :�u# �/%0(S�����(31�DE�/?0(�D:�*�CDE :(S�R1* :�w�jDE�T"&�OrE(31�DE"& x*q|�bED� :"9%���>1*(*�)�7c{�� �D5D�;�*�T >�8rEr��*1�D:}@{R�T��%mD�;�! S13#T(j7R�T1*(3#

HA

L author manuscript inserm

-00243083, version 1

%���"&�!�21m���*#T(*'�*�o�(�D�;�t�(*'��^P'oP{�T�+�j�/��%�D�"O�T�3DE :(91*�*#�#w@A#T(3 K :��13�7�jDE"& RhDp;0(�D`�T��D�@+ E�)# ��(3�mDE"o�&@{1*# ��(3 �Dv :(*�R#T"&1*(8Dv� "&��\D�;���

�T��9@1�DE�2"&��"&r�%���+�aDE :(S�R1* :�w�jDE�T"&��(S��)DE �(*�R#T(8DE�T"&��"$r�� :"*DE�*�/�$�D�;�(8D�1*(*���!"��9@A#�(�DE�O��7@ �"&��(3#!�@ v?�w?�(j#K�/������;�(*��19�T��%

��7@ :"*DE �"3�+;�T1a�@��$�"& �D:�5�@��$�0 ��67R�T��%)(*�+"3�&DE"��� �"& !(9rErE�81�D��T��%O��7@ R"9��(j#�EDv E@1�D�@� ��jq\�bED� �"3%+��� 1*(9�)(3# R"O(91�D`?�� E') :(���2�j#2'

D�;� :"9@+%�;���"&��%���"&�!�21O�!�*1*;�(9���/��em�w�3D��8 �(31�DE�T�$%��j�T R��1�D:#T'�t`� Dp;�?0(9 :� "9@{C�/�SDv :(31*�*#2#�@+#�(9 ~R�w%���(3#2�T��%��(8D�;$t�(S'm�T��13#/@���w��%

�!�LD:"&%+��� (91�DE�T?�(8DE�*� � �"6D��*�w� ��T��(j�� ��_oy�F����:� 1�yh_aF ��6��+"&���w?�3�v�*# ���!���jD¥P�T�+���T��% � :"*DE�*�/� �E,I4��N].�:� (*���

��;"����;�(�DE� �&'#T�T�+"07�LD:"&#����p��T��(j��^��F��:�����:��D�;+�8 R�7P'a(9rEr:��1�DE�T��%a�T�+���T :�*1�DE#T'~Dv;�KDE �(*�R1* :�w�jDv��"0� "&rh7��?�8 �(3#."*Dv;�8 5DE(* v%0�RDz%����**q

�bEDE �"9%���e1*(9�e(91�DE�T?�(8Dv�V7�*# ��1�D:�*���T�3DE �(31*�*# #w@#T(3 ���T%���(3#T�T��%>�{(�D�;&t�(*'5�����A����&�T��%u"&�!D�;�` R�819���&D:"& ��@�P&D�'&�{�5PA"9@�+�{q0y��"*Dv;�8

�"&���13#T(&�R�T1*(3#+�!"��$��"�rN�*EDE �"&%���K(31�DE� "0�V(�DAD�;�5�!���KP �(*���;�(j\(9# R"�PA�*���K� �"3�A"���*�K�/��?"&#T?�T�$%�Dv;�.PA�T��&�T�$%!"�rN�*EDE :"0%����D�"

�!�*�KP �(*���3��(j7R"&13�T(8DE�*�` :��13���&DE"& x��0�"��R�wP#T'K(8DADp;0��1*(*?�*"$#�(9�5# ��?�*#Eq

]."*DE;¡�N4 �@�PjD�'&��*«13"9@{#T��PA���T��?+"�#T?�*���/���*EDE �"&%������7@ �"3�+ :"*D:�*1�Dv� "&���(j��@�%&%�*ED��*��P�'�Dp;��� :"*D��81�D�� "&�¡"�r

;�w���"�1*(9�`�(3#���7@ :"&�ZP�'!(9%0"0�� ED:.r�"& b�*�LD�;�� \�N4α

"& b�|4β

�$(*%�(9���ED\�7c13�LDE"*D�"9c� 13�E�/��9@13�*�>�j(9�K(*%�5(9��K����(8Dv;!�TU ��q���7�T��%

�N4α

(S�0�β

���"&1S�"9@jD\�!�T13�*�A�N4α

�+�+"6D\�N4β,

t�(&5�;�"&t��!DE"KPA�� �� �3@A�T :�*�>r:"& ND�;�5�+ :"*D:��1�D��T?�`�*rEr:�*1�D:�"&r.�6vDE :(9�j�2"�#G(S%0(9�T�ED

� R1*;���!�T(&�E�T��9@19�*�K�T� ��@ �' � d��q�����DE;+�Y"*Dv;�� �;�(*����9D�;�.P+ :(3�/�$\"$rk�|4β

�&�"&1*�+"3@&D��!�T13�5��c+;0�wPA�LD:�*�`(*�!�T��1* R��(jR�5�T�K(*�"0�jDE"*DE�T1

13��# # `�T�eDv;�K?+���SDv :� 1�@#T(9 Y�9"&��*`"&rbDv;�!19�8 R�7P :(9#N13"& �Dv��cuDE;+(8D� :�*�@#LD:���C�T��(SP��"& ��V(9# �LDE� �*`�T�uP �(3�T�m����?�*#2"3�+�!���jD � ���q��N4β

%�������� R v@��jDE�T"&�Ct�(jz(3# �"�r:"9@�+�!D:"C�T�K�(9�T Y"9�jD��T�K(3#.��(�DE�T(3#\# �8(9 E���T��%m�T�mr:���K(&# �>�!��19�6�|�@%$%�6vD:�T�&%uD�;�> :"�# ��"&r��\4β

�w�

�!�*���T(8DE�/��%V#2�8(9 E��T�$%V(S�0�`�!�S�!"& :'K�7c{�� �D��*��P$'!�6EDv :(3�&� "&#� l ��q

����DE;��;&@+�V(9�Kr:"& R��P �(3�w��&P+"6Dv;K�N4-�@�P&D�'&�{�*\(3 ��.� ��*��"&�!�T��(*�3D�#T'!�7c�� :�*�7�*�K�T�!#T�T�KPA��13�� R�*#T(8Dv�*�h(9 :��(j��$(3#LD�;�"9@%$;�D�;+�*'

�;"&t �j� ED��w�1�DK��� EDv :�wP�@jDE�2"&�O�(8D Dv�8 v�$Sqbf|;��~�|4α

�K4b<}y ��c$� R�6��� "&�)(*���+�8(9 xKDE"O��"0�!�T��(8D��~�T�aDv;�C;�'&�A"6Dp;0(9#T(3�`@G�(*���

(*�K'�%+�j(9#T(j�A�w��$��1*(�DE�T��%KD�;�(8D�D�;�α

�E�@$PjDE'&�A���!�/%�;3D\�!"��9@{#T(�DE���+"6D\"&�+#T'����@+ :"&��(3#�13�*# #��{"9��@+#�(�DE� "&���T��?+"�#T?�*���T��(*@jDE"9�"0�!� 1

(*���! ����+ :"��9@1�D��T?�z��7@ :"����+��"&1* :�T��zr�@�1�Dv� "&�\P�@&DN(3# 7"!(9 :��(j.�/�h�A#T� 1*(8DE�*�>�T�u���!"*D:� "0�0(9#G�T�3D��8 v� :�RDE(�DE�T"&�e(S��`� :"$13�*���w��%Gq&���

1*"&�3DE :(&ED:�9D�;��5;�w���A"&1*(3�`�(9#Ar:"& ��V(�DE� "&��A���3DE"& v;�T��(3#A19"j �D:�7c{�+(S�0��Dv;�(3#T(9�h@A.(*�$��8(9 kDv"`P{�5�N4β

�&"&�!�T��(9�3DN(9 :��(j��A�@$%j%+�3EDE�w��%

(O��@jD�(�DE�w?�a �"j#2� rE"& u�|4β

�w��1*"&%���LDE�T?+�m� R"&13�*�7���$%$�z���91*#�(9 :(�DE�w?�o�!���!"j �'�(*����!"*D�"& ur�@���1�D:�2"&���T��% �R� ��q�M|� D2DE# �O"& ��"

��c$� R�6��� "&�!"&r��N4β

� I���xD��*1�D��*�h�T�! ����+ :"��9@1�D��T?�\D:� ��@A�*.�@1�;K(j�D�;��@jD��� E@{��0t5;�� x���N4α

;�(j|P+�*���eR;�"&t��hDv"`�!�*���T(6Dv�bDv;{�

R�7c�@(3#\1*;�(9 :(31�Dv�8 ��/vDE�T13`"�r��*EDE :"9%���a�*rEr��*1�D: ��� ��q+���LD�;m�!�T��/�V(9#N�A�8 ��w�;�� :(9#Z�� �����8r�r:��1�D:��|�N4β

R��# �*1�DE�/?�!(9%�"&�� ED:`1*"9@A# �

D�;&@{|P�����3R�T%��+�*�YD�"��+ :"&�!"*D����!���!"& �'Kr�@��1�DE� "0�V(S����+ :"*DE�*1�DE� "0�V(S%0(9�T�ED���7@ :"$����%����� :(�DE� "&�K(j��"j1*�T(�D:���`th�LD�;Ky��!q

��� � � � � ����� �� �� �� ��� �� ��� ��

B��?+�8 �(3#G�|4Y�α

�A"&#T'��!"& E�+;� R�!�;�(9?�5PA�*���~� �����3DE�2rE� �*��(*���# �T�$��*�hD�"!(}?0(9 :�T�RDE'u"�r."9@jDE19"&�!�3����T��13#w@{�$�T��%e19"&%���LDE�/?{�

�T�`�(3�T ��!���3Dh(S��a�$���e���3D:�T(&�\1*(3 :�&� "��p?0(&R1�@#T(3 z�(�D�;�"�# "&%�� �&��\"& `�!"����Tr:�T1*(8Dv� "&� "&r5D�;�C�*rEr:�*1�D:>"&r`��c{"9%���"0@{>�6EDv :"&%���)"&�

HA

L author manuscript inserm

-00243083, version 1

#T���A� ��# ��?�*#�5�T�~"&# ���� �th"&�!���Gq&���LD�;u R��%�(3 ��VDv"e19"9%���LD:�/?�K�T�`�(3�T ��!���3D.(*��������!���jD���(&�+D�;��h�N45�α

���KBb���E��X�l�f p,��2F+?&@�E�:�:�

���KBb�8�E��d��uy p,s����P(9�!�T���T�3DE :"&�¡�8�5(*���aDp;�C� :"0�!"6D��� e ���%�� "&�-f|y :�7�A�8(�DK�"$#�'$�!"j v�;+�/��!�;0(S?�m R�819�*�T?�*�aDp;�m�!"��D

(8D Dv���3D���"0��q&f|;�*���R(9�!���A"�#w'��!"& E�+;� R�!I;0(S?�5(&#/�"`P{�*�����T�K�# �T1*(8D��*�K�T�!1*(9 :��� "9?�(j�1�@{#T(3 |��(8D�;�"�#2"&%�� �6|D:"0%�xDv;�� Nt`� Dv;!���KB\�8�

U���Of 2, �w���T�3DE �"&���8�>,\y x�7�A�8(�D:�K(S�0��(��"&?�*#}�{"$#T'��!"& E�+;��/�� �T��� :"&�!"*D��8 m] �\�8X �jX�f � ��1*r�q�� X�E��qzfN;��OD�th"

�"�#w'��!"& E�+;� ��}��!"�ED.rE R� �9@{���3DE#T'u(&�R"&13�T(8Dv�*��th�LD�;~1*"&%$��LD:�T?+�h�T�K�+(3�T ��!���SDI(*��u�$���!���jDE�T(!(9 :�`FA?&@�E�.(*�+���zP(3��g+r:"& I�!"0vD

1*(jR��13"&�3DE �"�#AED�@���2�6����T��13#w@{�$�T��% �j�5DE"`W�W�K1*(&R�*R�:��(`R�T%���� rE�T1*(9�3D��T��1* x��(j7���/��Dv;�5rE :� �9@A���13�5"&rADE;�*7�ZDpth"��A"�#T'$�!"j v�;+�/��!

t�(j�"9P{7�8 v?�*�O�T�O�(8Dv� ���3D:>th�LD�;-��A"& :(3�&�T1my�� �R�������8���q����#/' "0���vD�@�&'-�&� � �"*Dh ���?��(j#�(*��')(&�R"&13�T(8Dv� "9� �R�7U ��q\fNt�"

ED�@�&� �*`;�(9?�}P{�*���a1*(9 : :�T�*�m"9@jDz"&��F�(3 v�0�/�$7"&�G� K�&� 7�8(&��>th�LD�;O�����!���jDE�T(g|"9��u���8�m1*(&R�6����;"&t`�*�m(*�m(j�R"&19��(�DE� "&�mt`� Dv;

FA?&@�E�\P�@&D\�"*D���P(9�\�"�#T'$�!"j v�;�� �� �R��� �:��t�;+�8 R��(j.D�;+�K"3D�;�� Y��UN�z1*(jR�*R���;"&th�*���+"e(&�R"&13�T(�DE� "&�ut`� Dp;^F�?&@�E� �R�8d �8q�f|;�

"&�#w'a�+ :"���A�81�D��T?�u19"9;"& �DhvD�@�&'O"jr`W�&W+dm�+"3�+�����e���3D��*�at`"&�!���)"&?�� V��d='��(3 RK1*(9 E :�T�*�a"9@jD�D:"o�j(�D:��(9#/7"a�@+%�%�*:D�K(*�

(j��"j1*�T(�DE� "&�`P�RDEth�*���KF�?&@�E��(*�����P(9�G�+"j#/'��!"& E��;� ��}\(S��`13"&%&��LD��T?���$�*13#T�T�� �R�8���q

y�R�T%��+��r��T1*(3�3D.�/�SD��� :(31�Dv��"0�u;�(j5(9#/�"!P+�*���~"9P{��� �?�*�>P{�RDvth�*���!DE;�*7�YDvth">�"�#T'$�!"j v��;� ��e���FA?&@�E�."& ��P+(3�:�A(S���VDv;�

(*�"&# �w�"9� R"*D��8�T�!�εU!(9# # �*# ����y5�A"&�b�

εU��|�T�hDE;+�Y �� R�!"�r|����?{�*#2"3�A�T�&%erE(9�K� # �T(3#�y���� �54¡���3qL�K1*"0�h�(9 :�*��D�"!�@�P �7�*1�D:\th�wD�;"9@jD

D�;�*���%���+"6Dv'&�{�*.(S��K��?���>;�w%�;�� brE"& \�8(9 :#T'!"&�7�xD ��4)W�W+� �R��l��q�B$@1�;!(*�!�/�SD��� :(31�Dv��"0�K;0(&\(3# 7"�PA�*���!r:"9@+��hr�"& b#T(8Dv�Y"0�$7�RD

��"& :(9�&��1`�����!���jDv��(&�$t�� Dv;K(3�!�/�01* R��(jR��P�'el�q �$��r:"&# �K�T�>;0"0�e"&�*'�%+"3@A\y5�{"&�b�εU��w��?�2�3@+(3# \th�LDv;�Dv;�*��5�N4

α �"�#T'$�!"j v�;+�/��!

�R�8���q$���e(`%����RD���1KED�@+�&'�th�LDE;u�����}�(8Dv�����3D:Yt��LDv;�y �`�A�LD\;�(jIP�*���ur:"9@��+�hDv;0(�D\"&��5�(9 �DE�T1�@#T(9 :#w'e(9# # �*# �`"&rkDv;���N45�β

%����

��(3#T# �*# �`d&�b19"9@{# �>(3# R">(31�D\(j\(`�� :"*DE��1�D��T?��rE(91�DE"& .�T�!y���� �54�m�AqLd�d&� �R� � �Rq&y��"*DE���3D:�T(9#G�T�3D��8 �(31�DE�T"&�>P{�RDEt`�*���VDv;�67�`�N4α

��FA?&@�E�.(S�����P(3�E�.(S����N4β

�E�A� �5fb4 �"&#T'��!"& E�$;� R��by`#T@�E�\�"�#/'��!"& E��;� ��}�(3���KDv;�h �� R�~"&r�����?�*# "9�A���$%uy����El��z�!�*�

(*���m����W}th"&�!�����T�1*#w@{�$�*�K(j.1*(&R�*R��;�(jI(3# R"`PA�*���! :�7�{"& �Dv�*� �R�8X��P�@&DN�T�hD�;+�/I1*(jR���0">�T����7�A��������3DN(&�R"&13�T(8Dv��"0�!13"9@{#2�`P{�

rE"9@��Aq`HK����13�*�KD�;����c� ED����13��"jro13�� �DE(9�T���"$#T'��!"& E��;+�/��!�"�ra�N4 1*"9@A# ��13"0�SDv :�wP�@jDE�)D�"�(�R�w%���Tr���1*(9�3DE#T' �w�1* :�*(&R�*�

�@{R1*�7�jD��wP� # �LD�'a"�r�th"&�!���~D�"eDv;�KPA����*r���19�T(3#.�E"& 5;�(3 ��Kr�@{# �z�8rEr��*1�D:K"&r��*EDE �"&%�����|(��"��7��P+� # �LD�'atz;0�21*;m;�(jz�"*D�'�xD�P�*���

��c$�{# "& ��*�YD�;+"j R"9@�%�;+#T'Gq

B � ������ � � ������ ��� �� ��������� � � ��� � �� �� �� � � �

�bEDv :"9%��� 1*(3� �!"$�3@A#T(8D������@+ :"*DE :(S�R�!�LD DE�� aD�@+ E��E"&?+�8 «P�'����?�� :(9#C�!�*1*;�(9���/��e����T��?"$#�?+�T��% ��7@ R"*DE :(S�$x�!� D2D:��

�'��3D�;�*7�/7��� ��8��@��&DE(*��*�$ :�*# ��(j7�6�$ :��13�7�jD�"& N�����R�LDE'�$ :��13�7�jD�"j |���3D��8 �(31�DE�2"&��������*'$�V(�D:�T15 :��%&@A#�(�DE�T"&���"& �%+����5��c�� :�*�7� "9�Gq&_a"& :�

����13�Tr:�T1*(&#T#T'���6vDE :"9%���¡1*(9� @$�{�� :��%&@A#�(�DE��1S;"�#T�T��� �%�� 1�(31�Dv��?��LDv' P+' �/��9@1�D:�T"&��"&r�1*;+"�# �w���(913�RDE'+# Dv :(*�Rr��8 �(j���(S��

(31*�RDE'�# 1S;"&# �T��K�*ED��8 �(jR�K�w�!Dv;��P+(jR(9#krE"& R�7P :(9�����(*���u�/�01* R�*(&R�w��%!D�;�`;�T%$;^(9rErE�T��LD�'~1�;+"�# �T��z@��jDv(*��`t�;�� 1S;u�/�(! :�7%&@{#2(8DE"& E'

:(�DE�«# �T�!�LD:�w��%�ED������T��(313�RD�'#T1S;"�# �T�+�-�'��3Dv;�67� �TW���KW|� ��q �bED� :"9%����1*(*��(3# �"��T��1* R�8(&��aDp;�) :(�DE�)"&rm����%� :(9�&(8DE�T"&��"�r

HA

L author manuscript inserm

-00243083, version 1

�!"&�"&(9�!�T���"9c� �&(j7�)��_ay��5�:�Vt�;�T1*;�"�1*1�@ Rm�T�-Dvth"���R"&r:"& ��}��Vy�(*���]��`(*�� �!��DE(*P+"�# �T�3�*o1*(8DE��1*;"$#�(9�!�T�+�6��Q¤�� Â��

R�� :"*D:"0��T���Ed��2H`fb�:���&"9�(9�!�T�������y��:���+"j �(3�& :����(9# �T��!�2<Kyh�Ith�LDE;m�&� rEr:�� R���3DY�@$P{EDE E(�DE�`� :��r:�� R����13�*��TW�W ��qA���eDv;�}�V(913( �9@A�6�

"&��>�!"&�3Dv;a"jrz�6EDv :"&%���m :�7�A#�(913���!���jD5(9#T"&������*1* :��(j7�*��D�;����c$� R�6��� "&�a"&r5_my ���pyh��P�@&D��0"*D5]��|�T�uDE;�> :(S��;��!�&@A1*# �7@{��

t�;�� R�8(&����T�C;�'&�{"*D�;�(9#�(9�!�T1��&@19# �*��PA"6Dv;~_oy�����y (*�+�~]��K4b<}y th�8 R�>���*1* :��(j7�*� �TW����W�U ��qA�v����"& RR(3#N �(*��;+�6�Nx;"& �D:�����

�!"&�3DE;��:�{P�@jD|��"6D\# "0��%�b�Ed>�!"0�SDp;$7�.�TDE�8 �� �6vDE :"&%+���^�7c��A"��@ :�z���*1* :��(j7�6�_=y �z��y��+ :"*D:�*�/�e�7c�� R�67R� "&��A(S���K� �"&%�*ED:�� R"9�{�

�@����+# ���!���3DE(8DE�2"&�Ot�(&>t��LDE;"9@jD}�8rEr��*1�D�qN�v� 13"0�SDv :(jvDp�I_my�����] � :"*D��*�T�Ot�(j}@���(3rEr��*1�D:�*�=P')�*EDE :"0%��� (9# "&��*�\P�@&Dh�LD`t�(&

�T��1* R�8(&R�*�Kth�LDv;e�;"& �D��N"& \# "9��%{�TD��8 ���� :"0%�6vD:�� :"&�+��x@����A# ���!���jDE(�DE�T"&� �TW�U���q&fN;������Tr�r:�� x���3DE�T(9#G�7c�� R�67R� "&��"jr�D�;�`����%� :(9�&�T��%

����*'$�!�6��/��Dv;��� ��67���13�C"&rVvD:�� :"��2�0��@$%�%�*ED:>(m1*"&�K�A# ��c)19"&�KP�T��(8Dv� "&�)"&r`%�����DE :(S�$�1* :�w�jDE�T"&��\�+"0vD:�TDE :(S�R1* :�w�jDE�2"&��(3#

� :"&19�6���T��%��(*�����@�PAEDE :(�DE�sr:�*�*�9P(91����!�*1*;�(9�� ��} t�;�T1S;��K(3'��+#�(9'�( :"&# �s�T� 7�8 R"*DE"&�+�T��"& �1*(�DE�*1*;"&# (S�!�T��

��7@ :"*DE �(*�R�!� ��� "&�K(*��z;���19�6�$�K"�"��`(*��`13"9%��+� D�� "9�!�T�`;�@+�V(S�$Sq

����D�;���!� �&P �(3�w�!��� :"*DE"&�+�8 �%�T1��'ED����}�+�*EDE �"&%���!� \�T�`�{# �T19(8DE���K�T��D�;�5�w��9@{1�DE�2"&�V"$r{Dv E'&�jDE"9�+;0(S�h;$'�& :"9c'+#�(&R�*��(S��YDp;{�

:��%&@#T(8Dv� "&�!"&rNd��2Hhf~Dv E(*���"& �Dv�8 R\(*��Kd��2Hhfo :��13�7�jD:"& bx@�PjD2'&�{�* �TW�U ��q9�bEDE �"9%���! :��%&@A#�(�DE�*�D�@ E�+"&?�� N"&r �zy��T�K;�'&�A"*D�;(3#T(S�!� 1

�&@13# �*�\(*�+�~�T�m�+�T%� :"�EDE ���(�DE(3#\(*���C�!�*�"$#��/�KP{�T1 ��y��'$vD:���!`(9�0�m1�;� R"&��� 1u�*EDE �"9%����(&�&�!�/�� EDE :(�DE�T"9�a���*1* :��(j7�6����K(*��� �zW

:��13�7�jD�"j 51*"&��19���SDv :(8Dv��"0�$SqA�bEDE �"9%���~(3# 7"urE(31*�2# �LDE(8DE�*z(*�`�;�RDE(9�!�T��*��"& Y(S�"&�!"& E�$;0�/��3�EEDE�T�K@A#T(8DE�*� ��y� ��*# ��(j7�jq�B$'EDE���K(8D�� 1

:��?�� ��tV�"�rND�;�K�*rEr��*1�D:5"�r��6EDv :"&%����;0(S?�K13"9�1*#w@A���*�KDE;�(�D.�6vDE :"&%+���$z����;�(*�+13�`(3�& R����8 v%�T1K(31�DE�/?�LDE'�P�'~�/�01* R��(jR�/��%!D�'� :"���/�{�

;�'�& :"9c+'�#�(&��C(31�Dv�T?�LDE'��rE(31*�2# �LDE(8DE�w��%O<Ky� R�8#2�8(&��*��(*��)�/�019 :��(jR�w��%�%�(3#T(*�+�T�)�K4b<}y �T��R"0�!�m���@ �"&��tz;�T1*;��V(S'-(3rEr��81�D

�"& :(9�j ������ E%�T1.D:"0��.P�'K R�*�9@13�T�&%�<Ky� R��@$�jDE(*�+�jq9[A@� �Dp;0�� ��!"& x�*�$�6EDv :"&%����DE ��8(�DE�!���3DADE �(*�R�T���3D:#T'K��"&tz�$�� R��%&@A#�(�DE�* � yh]Iy�(S��

]. :(9������`�8 ��T?�*��<>��@ R"*DE �"3�$;�T1�[G(31�Dv"j a��]���<K[G�C(31�D��w?�LDE'��T���T��;+��P+� D�"& E'��T�3D��8 v���@ :"0�$Sq����LDv;�T��Dv;�«%#w@jDE(9�K(8DE�� :�*19���jD�"&

rE(*�!� #/'$�9<!�p�!�xDv;�'�#����h��(&��(3 Dv(�DE�Y�T<K_ ��y��� :��13���&DE"& x��0y�_aFAy� :��13�7�jD�"& x\(*���z��(3�T��LD��� ��*13�7�jDE"& x.��(&|t��*#2#(&.R�w%��V(z :�*13�7�jDE"& RR�

;�(*?��(3# �"zP�*���!�����!"0�{EDE �(8DE���YDv"�PA�Y7���7�LDE�T?�\D:"KEDE�� :"��2���!"��9@A#T(8DE� "0� �TWd ��q

� �T?+���=Dp;�Cth� ���C :(S�&%�m"&r!��r:r:��1�D:�"$r!EDE�� :"�� � ;0"& ��!"&��*�"3�«���@+ :"*DE :(S�R�!�LD D��8 ��'EDE���e���(S�0�O(9#/�")"&�O��7@ :"&��(&#

"& E%�(*��T�*(�DE� "&��(S����'���(*�jDv"3%+����3�� ��e�h@A#LDE�w�{# � ���@ �"3�+ :"*D:�*1�Dv�T?���*rEr��*1�D:«1*"3@A# ��PA���7c��A�*1�D:�*�¡"&��19"&%����LD:�/?��r�@��1�DE�T"&�

�2�"*DE(*P+#T'~(8D2DE���3DE� "&��(3#|�!�*1*;�(9�� ��}���# �8(9 E��/��%~(*�+�u�!�S�!"j �'��:�|#�"$13"&�!"*D�"j 5(91�DE�w?�LDE'���(9�w������7�LD:�w?�LDv'$��(*���?&@#T��� :(SP� # �LD�'uDE"

���A� # �7�{�' �E7�*�!r�"& Y ���?� ��th �TW�W��W����Wl �E��qG,."9%���LDE�/?�!r�@+��1�D:� "0�0�/��%~(9���Cy �¡�K(9'uPA�!�!"$�3@A#T(8DE�*�>DE;� :"9@+%�;~(913�RDE'�# 1S;"�#T�T��

(*���C� D�5�A"�R�LD:�T?+�K :"�# ��"9�a�'���(*�jDv"&%����3R� `�T��DE;�};�w���A"j1*(S�K��@{��kt�;�T1*;C;�(jz(!�+�T?�"6Dv(3#N R"&# ���T�m���819#T(3 :(�DE�w?�K�!�S�!"& :'��TW �j�

WX��q5]\'��!"��9@#T(8DE�T�$%-D�;�O(31�DE�/?�LDE'�"&r!Dv;�O13�� R��PA�*#T#�@+� (*���)D�;�O�+�T%"�EDE ���(9#K(*�����!�37"&# �T�KP�21)��"9�(9�!�T��� E%�T1-x'$�DE���e��

�6vDE :"&%+���$Z;�(*?�5�*rEr:�*1�D�\"&�K�"& ��V(9#(S��h(SP��"& ��V(9##2"j19"&�!"&DE"& N(31�DE�w?�LD�'GqSHh�T%�;!#2��?�*# ."&rN�*EDE :"0%���!��c+(313�� EP+(8DE�5�'��K�jDE"0�}I"�r

FG(* v�0�/�$�"&�k� 5�&� ���(j7�*�Atz;�8 R��(j�# "&t�# ��?+�*#/�rE(913� #T�LDE(8Dv�K�j"9�(9�!�T�+�8 �%�T1`r�@�1�Dv� "&�Gq�[��T��(3#T#T'�+P+'��!"��&@#T(8Dv�T��%VDv;�h7�����LDE�/?��D�'u"&r

��W�� ��819���jD�"& x\�w��D�;�.P+ :(3�w��+�*EDE :"9%���\(S�����(3 GDE"z;�(*?���T�K�A"j �DE(*�3D���7@ �"j#2���jDE�T1j��# �/��5�*rEr:��1�D � �����q

HA

L author manuscript inserm

-00243083, version 1

���KDE;�`"*DE;+�8 I;0(S����+� �"&%�*ED��8 �"&���(91�D:�(j�(`th��(3��(3# #2"0vDE�* :�T1`�!"��9@A#�(�DE"& ."&r � y�].y�� �(SP�T# �LDE'KD:"��T��1* ��8(&��`1�;# "& :�2��

1*"&��9@1�DE(S�13�`D�;� R"3@$%�;^Dv;� � y�].y��^ R��13���jDv"j z1*"&�K�{#2��cot�;�T1*;m13"&��r��8 R`"&�~�+ :"&%�*ED��8 �"&��>(*��m�LD:V�!�xDE(SP"�#T�LD:�*`(*�m(31�Dv� "&�

R�T�!� #T(9 !DE"OD�;�(8D�"&r>P{�����3"$���T(3�3�7��T�+�6C(9��«P(3 vP�LD�@ E(�DE�6C(S�����V(9'�13"&�3DE ���P$@jD:�CDE"��LD:C(*�3DE����13"&��?&@# R(S�3D>� :"9�A�8 �DE� �*�� ��� ��q

FG �"3%+�6ED��� :"&��o(*�� � :"&%+�6ED��T��1*"&�K�A"3@+����(3# "&�+� � �&W ��"� ��w��13"&�KP�/�0(�DE� "&��th�LDv;��*EDE �"&%��� � ����>(3 :�o(3# 7")1*(*�(SP# �o"�r

����;�(*�1*�/��%�Dp;� �zy �'ED����^q

� ��� � �� ����� ���� ���� � � � � ���������� �� ������ � �

�bEDv :"9%���);�(j^(m����@+ :"9� :"*D��*1�DE�T?�m�*rEr��*1�DK"&�-"*Dv;�� e���*1*�2rE��1=�!�*1*;�(9���/��e� ��*#�(�DE�*�mD:"O19"&%����LD:�T?+�m�&'Rr�@��1�D��T"&��.P+'

P# "&1*�+���$%=Dp;�~(91�DE� "&�)"&rK�+��@ �"*D:"9c� 1C(*%+���SD��"& !�T�&;�wPA� Dv�T��%�Dv;�*�T `%����� :(�DE� "&�Gq|� Dh1*(9�O�"*DE(SP#w' �+ :"*D:��1�DK1�@#LD�@+ :�*�O���@+ :"9�

(*%�(3�w�ED�Dv;���+��@ �"*D:"9cA��1K�*rEr��*1�D:�"�r�D�;�K�7c13�LDE(�DE"& E'���7@ R"6Dv :(*���V�LD D��� .Mb��%#w@jDv(*�K(8D���� �&U �."& ."�r�DE;+�h�*�7���SD��T(3#�13"&�EDE�LD�@A���3D."&r

R���� #2�5�{#T( �3@A�*5�T��y��h��D�;+�h(9�K'�# "�� �β

��yβ

�|�A���jDv� ���*�Atz;� 1�;u� �r�"& :�!�*�KD�;� �"3@+%�;KDE;�`�T��9@1�D�� "9�~"&r."9c� �&(8Dv�T?�KEDE :�*� � �$d��q

fN;��C(*P�2# �LD�'-"&rm�8lβ

�E�*EDE :(9�&��"$#ZD�"O���T R�81�DE#/'«�1*(3?+����%�C;�T%$;#T') :��(31�DE�/?�mrE :�*�C :(9���T1*(3# ���(*���mDE;&@{��;� �*# � ���@+ :"&��(S%0(9�T�ED

��cA"&%���+"3@A\"3cA� �&(8Dv�T?���/�$x@{#LD:\(S�0�z��7@ R"9�0(&#+(*�"9�jDv"0��/7��� \�9@{�\DE"5D�;�.�+ x�*7���019�5"jrAD�;+�.�+;���"�#T� 1�y� :�T��% � �����q

f|;0�^%# �T(3#.19�*# # !"&r�Dp;��P �(3�w�a(3 ��VDv(3 E%��RD:Kr�"& VEDv�8 �"�� �m;+"j v�!"&��3��\(S���m�!�*���T(8D��u���TrEr��8 R���3Dz;"& :�!"0�0(9#���rEr:�*1�D:}�T�~Dv;�

:��%&@#T(8Dv� "&�u"&rkDv;�`����?�*# "9�+�!���jD\(*��>�#T(jvDE�T13�LDE'u"&r.��{��13�Tr�� 1��+��@ :"&��(9#A�A"3�$@#T(8DE� "0�$�(S����T�VDv;�`1*"&�3DE :"�#�"&r.�����"$1* :�T��`��?���3DR

�ER�*��r:"& � ���?� ��t �TW��E��q � # �T(3#.19�*#T#/}��c�� ��6�`(^�j@+�KPA�8 �"$r5� :"*DE�*�/�$5Dp;0(�D51*(*�CP{�� ���%j@A#T(8DE�*��P+'a�6EDv :"&%���}�T��13#w@{�$���$%ay5�{"&�b�

t�;�T1*;�� a�/�h�A# �T1*(8DE�*���T���!�S�KP :(S��Or:"& ��V(�DE� "&��(S���EDE v@1�D�@ E(9#`�#T(jEDv��19�LD�'�`(*�� %# �T(3#Kr���P+ :� #T#T(3 v'�(31*� ���T1«� :"*D��8�/��tz;"���

��c$� R�6��� "&�u�T��1* R�8(&��*�th�LD�;�P �(3�w�e(9%��T��%Gq��\EDE :"0%���5�T��1* R�*(jR��19�8 R�7P :(9#�%#w@13"�7�5@jD�� #T� �*(8DE�T"&��{�{"��R�wPA#T'!P+'u�T��9@A1*�T��%u%#w@19"���

DE E(*���+"j �DE�� m�u�w�=Dp;�m�����"*Dv;�*#T��(&#�13�*# # �"&r5DE;��P# "$"����2P :(9���oP(3 � :�T�� x�.(S���~Dv;j@A! R�7%&@{#T(8D��!D�;+�~(SP� #T�LDE')"&r�D�;��P :(9�w�=Dv"m@{��

%#w@13"�7��(&\� D�|� :�T�K(3 v'V���+�8 �%�'!R"9@ :19�jq�<>��@ �"��T�K(*%�/��%}vD�@��� �*\;�(S?��(9#/7"K�����!"&�EDv :(8Dv�*�YD�;+�� :"$# �5"jr|�6EDv :"&%���!�/�!�T��1* :��(jR�T�+%

P"*D�;� R��%�� "&��(9#!13�� R��P+ :(3#}P#T"�"���r:# "&t (*����%#w@13"�7�)�!�RD�(*P"&# � �� � ��l��E��X ��q5y ��*13���3DC :��?�� ��t "�r���7@ :"��/�V(9%�T�$% ED�@+�j�2�3

1*"&�1*#w@A���*�~D�;�(�Dh�*EDE �"&%���O :�7�{#T(319���!���jD�Dv;�� :(S��' ���N4�f\�5�K(9' ���*1* R��(jR��P+ :(3�w�ot�;�LD:�^�V(�D D:�� K# �*��T"&���Z;�(*?�u(C�!"$�3@A#T(8DE"& �'

�*rEr:�*1�D�"&��Dv;��?0(9 :�T"9@{�DE �(*�R�K�LD D��8 bx'$vD:���!\(9��h(9#LD:�� N :�7%� "0�0(9#�P+ :(3�w�K(31�DE�/?0(�DE� "&�`�(�D DE�� E�.�9@ ����$%!13"9%���LD���?+���+ :"&13�*�7�T��% �TU��:�

D�;&@{��@�%�%+�6ED��T��%mD�;�(8DK�*EDE �"&%���O�K(3'oP{�C�T�K�#2� 1*(8DE�*�O�T�OrE@���1�D�� "9��(j#I�#T(jEDv��19�LDE')�w�);��T%�;�� !"& ����8 `P+ :(3�w�Or�@��1�D�� "&�*qN[��w�0(9# #T'�

�6vDE :"&%+���$�;�(*?�zPA�*����"9P{7�8 v?�*�KD:"� ��*�3@+13�5DE;�`(31�@&D:�z�;�(&R�K"&r.(*�~�T��r�#�(9�K�K(8DE"& �'u :��(31�DE�2"&�u(*���(3 ��h(9# R"�(*P# ��Dv"u�T����T ��*1�DE#T'

�!"��9@{#T(�D:�u#2���A"9� :"*D��*�T�)# ��?�*# ��ZP�')���*1* :��(jR�/��%�Dv;�C# ��?�*# �"&rhM ��MZ��1S;"�# �*ED��8 �"�#�(S��O�T��1* R�8(&R�w��%OH���Mb��1S;"�# �*ED��8 �"�# �\t�;�T19;

1*"9@{# �C����1* R�8(&R��DE;+�K :� R�m"&r�(�D�;�� x"�R19# �� :"��� *q�fN;�� �(91�DE�T"&�C;0(&5P+�*���~;�'&�A"*DE;�*7���9�*�!D�"u13"&��r��8 5(>� :"*DE�*1�Dv�T?�!�*rEr��*1�D�r�"& �P+"6Dv;

?�(jR1�@#T(9 N�&���!���jD:�T(�(S����y���(j\(�D�;��8 �"�R13# �� :"�7� |;0(&|P�*���K�T�K�# �T1*(8D��*�`�T�hP+"6Dv; �TUN� ��q

HA

L author manuscript inserm

-00243083, version 1

¸

½B¦�±H¶>¯�¯�³R£[ÁG�A(`�+# �xDv;"& :(K"&rT¨l¦]¥@¨»§t£�«�(*����¨l¦�¥@¨l¥@«u��c��A�8 ��T�e���3DE(9#��j(�DE(�D�;&@{�13"0��?�� :%+��D:"��@����A"& �D\(`�"�R�LD��T?�� R"&# �K"&r

�6vDE :"&%+���$}"&�m?�(3 ���"9@{V���@ �"6Dv :(*���!�LD D��� h�'ED����e`(*��m"&�m�+��@ R"9��(&#br�@+��1�D:�T"&��/��%GqGf|;�*��>?�(3 ���"9@{V��7@ R"&��(3#.R'EDE���u`(3 ��

�"*DE(*P+#�'a�/��?"�#T?+�*�m�T��19"&%����LD:�/?��r�@��1�DE� "0�$�|t��LDv;m%# "9P(3#.��r:r��81�D�`"&��(�D D����SDv� "&��(3#\(*��C�K�+�3��T1�r�@��1�D�� "&���|(jzth�*#T#\(jV�!"j R�

����13�Tr:�T1¡(31�DE�2"&�� ��*#T(8DE�*�¡D:"¬# �8(9 E��/��%�(S�0�¬ R���!���KP{�� R�T��%Gqu�bvDE :"9%����(3# R"¬(*�����(3 )Dv" P�¡�T�`�{# �T1*(�D:���s�T��?�(& :�T"9@{

��7@ :"��$��%����� :(8Dv�T?����� 7"j ����� x�� �"*DE(SP#w' Dv;�����������3D:�T(j7���w� tz;�T1*; 1*;"$# �T��� E%�T13��7�8 �"6D�"9��T��� �%�� 13����"9�(9�!�T��� :%�� 13�

�"& :(9�j ������ E%�T13�|(*�� � y`].yh�� E%�21^x'$vD:���e`(9 :�!�/�K�(3�T R�*�AqG� D�th"9@A# ��D�;&@{`(*���A��(3 �#T�T��*#/'^D�;�(�D��*EDE :"9%���}13"9@# �m1*"&�$?��'�(

P����*rE� 1����@ �"9� :"*D��81�D��T?�C�8r�r:��1�D`�T� R��#�(�DE� "&�mDE"m�+(8D�;"$# "9%� �*��T�`�{# �T1*(�DE�T��%O13"9%���LD���?+�~�&'Rr�@+�1�DE�2"&�GqNf|;0� ># ��(3��}@{`DE"~Dp;{�

�9@{�*EDE� "0�~"&r.t5;��D�;�� 5�����"&1* :�/��hr�#w@1�D�@(�DE�T"&�5(31* �"07.D�;�`# �Tr:�3�E��+(*���(*���>�"*D ��@{ED."&�+�6�v"�rEr.�T�3D:�� E?+���SD�� "&��t`� Dv;u��cA"&%�S�"9@{

�6vDE :"&%+����T15�!"��9@{#T(�DE"& x��0�V(S'h�+#�(S'V(z :"&# ���/��D�;+�Y"9�7�xD|"jr�19"&%����LD:�T?+�Y�&� 7"j ����� N(*���K�����!���jD��T(q

���HG���6.*PL�6.?�,9OQ8;�'�$6=&�D'*98Q,=-u*P6�&)&�(+K�8 O$4<7R8$�5&}�;,�?�,s?'C]8;7>7;8J-'($&�6.?]-�6=N.?�45(;4<:P8�7>D�?=-�(;4�6.?94<?PN

f|;0�� R�`;�(j�PA�*���~(!19"&�R� ���� :(SP# �zP{"$�&'~"�r. R�*���(3 �1�;ut�;�T1*;�;0(&5r:"&1�@{7�*�C"&�!DE;�z�A"6D����3D:�T(9#k �"�# �>"jr�r:���K(&# �`%"&��(&�&(3#

;"& ��!"&��*��.�*��A�819��(9# #w')�6EDv :"&%�����\(&`�"�����P+# �u�!"$�3@A#T(8DE"$ xK"&rhx@{R13�7�jDE�wPA�T# �LDE'~D�"uD�;�C����?�*# "9�+�!���3D�(9��m(31*19�*# �� :(8Dv��"0� "&r

1*"&%���LDE�/?�>�(8D�;�"�#2"&%� �**q�[G#w@1�D�@(�DE�T"&�K�T�m%�"&��(&�&(3#\;"& ��K"&��*5DE;� :"9@+%�;"9@jD5 ���� �"��9@1�D��T?��#T� r:�*�NrE �"&��r:�RDE(3#.#2��r��hD�"m"&# �~(S%�3�

;�(*?�>"jr D�����P{�*���mR;"0t��!DE"~�7cA�8 �D.���T R�81�D�"& .�"*D����SD��T(8DE�/�j%m�*rEr:�*1�D�5"&�!DE;+�K13���3DE :(9#���8 �?"9@{zR'ED����}�k%�w?�T��%u :� 7�K�T�eD�@+ E�!DE"

P"*D�;��{�'+1�;�T(8DE ���1«�j� 7"& :���� xm�p�"*DE(*P#w'������+ :�*���2"&���^�py���13�*# �/��_oMb��4��LDE1�;� � �h�`�@�P��!�LD D��*��r:"& ���@�P+# �T1*(8DE� "0�0��(S���(3# R"��

(3#LD�;"9@�%$; #2�6�>��"&1�@+�!���jD��*�0�|DE"a19"9%���LD:�/?�u�&'Rr�@+��1�D:� "0��q�Hh"& ��!"&��(3#YvDE(8D�@A`�K(*' (9# �"��.(�D�#T��(jED`�w�a�(9 �D:�\�7c��#T(9�T�a%���+���8

���TrEr:�� R���019�3\�T�`?j@A#T��� :(SP�T# �LD�'�DE"`?�(3 :�T"9@{|��7@ R"9�{�'1�;+��(�DE :�T15��� R"& R���� x*q

[ �� ��� �� � ��� �� ��� �� � ����� ��� �� ����� ��������� ��� � �� ���

��?�(3 ��T(*��EDE�� :"�� ���;�(9?�o�h@A#LDE�w�{#2�a(*�+�-19"&�h�A# �7c��*rEr��*1�D:C"9�-P �(3�w��EDE E@+1�D�@ :�o(*����r�@��1�DE� "0��T��%)D�;� :"9@+%�;"9@jD�# �Tr:�*�

P��%�T�$�0�/��%�¨t¦Ê¶R§l¤v£�«�|�w��1* x��(j��T�&%a�j �(*�K(8DE�T1*(&#T#T'm(8D���@�P+�8 �D�'a(*���C13"&�3DE�T�&@A�T��%m"&�m�T�3D:"m����+�6R19���13�&q�fN;�}� :"&19�6�`"$r����c�@+(3#

���TrEr:�� R���SDv��(�DE� "&�C"jrI��7@ :"&��(9#N"& E%�(*��T�*(�DE� "&�~�w��?+"�#T?�*.D�;�!��*1* :�RD:� "0�^"$rNDE�6vD:"�ED��8 �"&��`(*���� D�51*"&��?�� x�� "&�~�w�3D:"��6EDv :(3�&� "$#G?+��(

(3 �"3�K(8Dv(jR�K�T�Cr:�RDE(3#\"& Y��(3 �#w'~��*"0�0(�DE(3#|#��Tr��6��t�;�� 1*;C#�(9 E%�*#/'~����D��8 ��K�T��3�D�;�� *�$�*r:���!�T��T�*(�DE� "&���K(S��! S�K(jR1�@#2�T��� �*(8DE�T"&���>"&r

P :(9�w��EDE v@1�D�@� :�*�(S���ur�@��1�D�� "&���rE"& 5��c+(3�`�A# �`P'C�T�1* :��(j��T��%C���@+ :"&��(3#\�����R�LDv'��w�eDv;�`�(9 :� �RDE(3#|(*���u?+�/x@(3#N19"& �DE�7ckqA� DI;�(j

P�*���~"9P{7�8 v?�*��r:"& ��7c(9�`�{# �*��Dp;0(�D.�9@ :�/��%!�A�8 ��T��(8DE(9#�����?�*# "9�+�!���SD���Dv;�`;����$�{"�1*(9�`��@{\DE �(*�R� ���3DE#T'u��c��+ :�*���*5�N45��+tz;�T1*;

1*"��T��13�2���Cth�LDE;aD�;+�uDE :(S�$�� ���3D!�7c�� ��6�7� "&�)"�rK(9 :"&�K(8Dv(jR�&q\�N4Y��w�)�K(&# �Cth"9@A# �mD�;&@{>PA�m��c��"���*�oDE")# "&1*(3#2#T')%����* �(�DE�*�

�6vDE :(9�j�2"�#+t�;�T1*;K13"9@A# �`# �8(&�5D:"K7��c�@+(3#A�&� rEr:�� R���3DE�T(8DE� "0�!"jr�;�w���"�1*(9�`�(3#AEDE v@1�D�@ ���(*���Kr�@��+1�DE� "&�Gq9�bEDE �"3%+���$\(9rEr:�*1�D�(9 :�*(j\"&r

D�;��P �(3�w��D�;�(8Do(3 :� �"*Dm�+ :�T�K(3 �� #T' �T��?�"�#T?�*�¡�T�  :�7� :"$�3@+1�D:� "9��u�@+1*; (joD�;��P(&R(3#ur�"& x�7P �(3�w��1S;�"�# �T��� E%+��1��'AEDE���e�

HA

L author manuscript inserm

-00243083, version 1

� À

;�w���"�1*(9�`��@{��|1*�� x�7P �(3#\1*"j �DE�7c{�N1*(S@�&(8DE�3�2�$@jDE(*�!����|�!� �9PA :(9���m :(��$;�!(S��uP+ :(3�w�aEDE����# "&1�@{`19"��8 v@# ��@{7�N(S�0�m���/�0(9#.1*"& :�

�ER�*��r�"& N :��?�� ��tV �TW$W��W+�j�$Wl�E��q

�bEDv :"9%���|;�(*?�5��T%$�0�2rE� 1*(*�3DN��rEr:�*1�D�\"&��Dp;�5"j v%�(*��T�*(8Dv� "&�K"�r�����?�*# "9�A�T�&%K���@+ :"&�\(*�+�h(91�DE�w?0(�DE� "&��(9#A�8r�r:��1�D:\"&�K�K(8D�@ ��

��7@ :"&�*q5f|;��'�1*(S��� :"&�!"*D��)�+��@ ��LD:�O%� �"&t�DE;�(S����'��(S�{R�OrE"& ��V(�DE� "&��(S����T��1* R��(jR�O1*;+"�# �T��� E%+��1«��7@ :"0�0(9#!�@A E?��T?�(3#Eq

�bEDE �"9%���� :��%&@A#�(�DE�*��'���(*�jDE�T1��+#�(&EDE�T13�LD�' P+'�EDE�/�K@#T(8DE�T�$%�(*c"&��(9#a�� :"9@jDv�T��%�(*�+� ������& R� Dv��1¡��{�w�� r:"& ��V(�DE�T"&���T��Dp;{�

;�'&�{"*D�;�(9#�(9�`@{�(*��),Iyu���'� �(*�!� �&(3#����@ :"0�$��w� Dv;�C;�T���+"j1*(9�`��@{��Yt�;�� x�ͲR¤ ¦R«d¥@«-�'���(*�{��mr:"& ��V(�DE�T"&���w��?+"�#T?�*!Dp;{�

�(3 Dv��1*�w�(�DE� "&��"&rN%�#w@jDE(9�!�T1�(319� ���+(31�DE�w��%hDv;� :"9@+%�;h<K_��zy� :�*19���&D:"& xSq&FA :"9%�*ED:�� :"0��5(*���A�8(9 x|DE"`;�(*?��Dp;�h"9���+"07�LD:�z�*rEr:�*1�D.i+�LD

1*(*���T��;�wP�LDC��7@ �"6Dv :(*���V� �7� "&��(*����# "&th�� CP �(3�w���7c{1*�LD�(*P�T#T�LDE'�Vt�;�T1*;�13"9@{#2���"*DE(SP#T'�#2�8(&�-Dv"��!"$"������6vDE(*P�T# �2�*(8DE�T"&�Gq

]��*R� ���37���LD�;0(&�(���� ��V(9�3DE# �/��%���r:r��81�D�(8D\D�;��R'$�0(S�jDE�T1�# ��?�*#EqAf|;�K(&�9?�8 R�����rEr:�*1�D5"&r�� :"0%�6vDE�T�`"&�m1*;"&# �T�+�8 �%�� 1>��7@ :"&��(&#

�T�3D:��%� �� Dp'�(&u19"&�h�+(3 :�*�oD:")�|4�f¡;�(j�(3# 7"OP{�*�����$���!"&��vDE E(8DE���«P�'�B+�T��%#2�mFG;+"6Dv"&���|�!� �R� "0� ,I"&�K��@jD��*�)f\"&�!"&%� :(S��;�'

��BF��b,\fb� �TU�W���q3�NED� :"9%���K R��%&@{#T(8Dv�6�D�;+�5�!"& E��;"$# "&%�'K"�r�(jEDv :"&1�'3D:�*.�w��DE;��;�'&�A"*D�;�(j#T(9�`@{\(*���`;�w���A"&1*(3�`��@{6i�@1�;K1*;�(*��%+�3

P�*�T��%K�A�� E;�(*�{I�T����� 1*(�DE�w?��"�r�%+# �T(3#A13�*#2#A(31�DE�T?��LDv'e�w�!�"& ��K(3#G(S���!# �*R� "&��v�T��9@13�*�!�'���(*�&DE�T15�{#T(&EDE�T1*�LDE'Gq&f|;0�z1*"��# "�1*(9#��2�*(8DE�T"&��"�r

�N4 t��LDv;m���@ �"6Dv :"9�;�� 1�rE(31�DE"& x>�<¤�� Â��N<K�� E?� � �"&t�DE;a[�(31RDE"& x��< � [��5(*���uD�;�*�T ` :��13���jDE"& RK�T�mP(&R(3#.rE"& ���P �(3�w�a1*;+"�# �T��� E%+� 1

��7@ :"&�z13"9@# ��(3# R"urE(S?"& ��T�3D��8 �(31�DE� "0�$�th�LD�;eDp;�3��`�!"$�&@{#T(�DE"& x5"&r�19�*# #N�@ v?�T?�(3# ��(*��KDv;�*�T �19"0�� R�7%&@{#T(8Dv� "&�u13"9@A# �>� :"&�!"*DR�

��7@ :"&��(9#{�@+ E?��T?�(3# �$���TrEr:�� x���3D��T(8DE� "9�K(*��z�#T(jvDE�T13�LDE'!�ER�*��r:"& N :��?�� ��tK �TW��&�$Wl�Rq

B�7c!���TrEr:�� R���13�*\�T�`P :(9�w�}EDv E@1�D�@� ���(*�+�hr�@��+1�DE� "&�K(3 ��bD�;�"9@%$;SDADv"h"�1*1�@+ N(j|(5 :�*�@#LD�"&rN�&��r�r:�� R���SDv��(9#A��c$�{"��@ ��5"jr��!�*�

(*���`th"&�!����D�"V7��cK;+"j ��!"&�+�6\�9@ ��T��%Kr:�RDE(3#+# �Tr:� �TU���q9fN;�� .� .�@�%&%�*ED��*��P+'!ED�@�&� �3\"&rN�T�����/?� �9@(3# |th�LDv;h%+����xD��T1���� R"� ����� x

%�T?��T��%m :� 7�hD�"~(SP��"& ��V(9#.# ��?�*# K"&r5(*�+�j �"&%���a��c��A"��@ ��e�9@ ��T��%mr:�RDE(3#.#T� r��jq�[G"& `��c+(*�`�{# �>%�T �#/Vth�LD�;a13"9��%+����LDE(3#\(&�j R�7��(3#

;�'&�{�� E�+#�(&R�T(ut`�8 R�!r�"9@���D�"u�A�8 �r:"& E�sPA�xD2D:�� �"&�uDE(jx�$}"&rh��(�DE�T(3#\(*P�T# �LDE� �*!�p�V(9# �3�TDv'j�+� 1*(3#.R�+��#2#/��Y(9���mt`"j RR��"&�~D��3ED:`"&r

?�� EP(9#A(*P�T# �LDE� �*���r����!(3# �.Dv'&�{�T1*(3#Gx�� # # R�N19"&�`�(3 ��*��DE"�DE;+�*� N@$�0(9rErE�81�D��*�!R� ED��8 R �TU�U���q � �T :# \th�LD�;!f|@ v�0�� .�'���& :"0�!�6��"&�hD�;�

"*DE;�� |;0(9����+#T(31S�e��(3 �#T'!(*��& �"&%���u��c$�{"��@ ���(*�+�K(3# �"!�;"&t�(&#LD��8 �(8DE�T"9�u"jr\�*EDE :"0%���!� �"��9@1�D�� "9�^�9@A�.D:"K(SP��"& ��V(9#k"0?0(9 :�T(*�

r�@���1�D:�2"&�Gq3f|;���'V(9 :��1S;�(3 :(91�DE�� :�T�3�*�zP�'K(h����13�Tr:�T15�+��@ �"�13"0%���LDE�T?�I� :"&r�� # �5"&r��"& ��V(9#�?�� EP+(3#A��� #T# ��$�T�K�(3�T ��*�`?� �@(3# �E��(8Dv��(9#

(*���>?��/x@(3# �2�A�8 �13���jD�@+(3#G(SP�T#T� D�� �*��A(S���!�T�K�(9�T x�*�}�"&��?+�8 vP(3#� :��#�(�DE�T?��DE">?�8 vP(3#��!���!"& �'Gq&y� ��819���3Db �(*����"&�!�2�3�*�!19"&�3DE :"$#�#2�3�

DE :�T(9#V��45,\fb�u�;"0th�*� Dv;�(8Dul��2'+�8(9 x�E"&# ��%+�� �# Cth�LDv;�f|@ E�+�* mB�'&��& :"0�!�Ot�;"�th�� R�O%��T?���-Dvth"�'��(3 RC"jr��N4�f��;+"&th�*�

�T�`� :"&?+���e���3DN�T�`?�� EP(9#(S��`��"&��?�� EP+(3#+�!���!"& �' �TUd ��q9yh��"�# �*R19���SD�%�T :# |th�LDv;Vf|@� E��� b�'&��& :"0�!�ZDv x��(8Dv�*�hr�"j |W`'�8(9 x�th�LD�;

(*���& :"&%+�����T�K�+ :"&?�*�¡��{�*1*�2rE� 1*(3# #/'��T�¡th"& :���T�$%��!�S�!"j �'�^t��LDv;��+"���w%��+��r��T1*(3�3Do1*;�(*�$%���T�¡?�� EP(9#u(*P+��#2� D�� �*��u��+(8DE�T(3#

1*"&%���LDE�2"&���(S�0�K�7cA�*1�@jDE�T?��r�@��1�D��T"&��T��% �TU���q

F ��� ��� ������ � � � � ��� � � ����� ��� � � � !� �� � � � �� � � �� � ����� ��� � � � � � � ���� ��� � � �

[G#w@1�Dp@(8DE�w��%�;+"j ��!"&�+�)# ��?�*# m(&�R"&13�T(�DE�*��t��LDE;-Dp;�O�!���GEDE E@�(9#K1�'019# �O;�(*?+�aPA�*�����;"&t��-DE" �!"����TrE'�19"&%���LDE�/?{�

HA

L author manuscript inserm

-00243083, version 1

�)�

��� :r:"& ��K(*��13�K�T��th"&�!�����;"&t`��?�8 R�+D�;�� x�`� �� R�*����3DE#T'��"u1*"&�7���$x@{5"&�!Dv;�`��(8D�@ ��h"$rND�;�*��K1S;0(S��%�*���tz;�T1*;~1*"9@A# �>P{�

:(�D�;+�8 b��K(3#T#A�T�!�K(*%$��LD�@{�$�8��(9��5DE;�*�T ��+"07R�wP{# �519"j � :��#T(8DE� "0�Kth�LDE;!��� :�T1z;�"j ��!"&��(9#A# ��?�*# *q$BjD�@�$� �6Z?�(3 E'Kt`� Dp;! :��%�(3 ��YD�"YDv;�

1*"&%���LDE�/?��D��6ED�\@{R�*�K(S���DE(9 E%�RDb�@$P ���*1�D:��$P$@jD�%���+�8 �(3#T#T'e�/����T1*(8DE�.Dv;�(8D�tz;���e�3EDv :(3�&� "&#�# ��?�*# .(9 :�5;�/%�;�*ED:�;¨ �l¤��A�9@ :�w��%hDv;�

#T(8DE�>r:"�# #T� 1�@+#�(9 h�2� �"j#2��r��8 �(8DE�w?�*���+;�(jR��"& �(8D.Dp;0�>�!� �$#�@&D:��(&#\��;�(jR�*�|�!"*D:"& �(S�0�C?+�8 vP(3#\(*P�T# �LDv'�(9 :����*���uD:"m�/�h� �"&?�*�|th�LD�;

# "&th�� :�/��%�"&r=�{�� :19���jDp@(3# �E��(�DE�T(3#��A�� :rE"& ��V(9��13��13"&�`�(3 ��*��D�"�# ��?�*# «(31*;+� ��?�*�¡�3@+ :�T��%¡�!���{EDv E@(�DE�T"3�¡t�;��� "&?(9 :�T(*�

;"& ��!"&���# ��?+�*#/I(3 ���# "&th�*ED\��fb(SP#T�e����q&MN(91��e"&rb1*"0�$7����@G.�K(*'KPA�5(8D Dv :�wP�@jDE(SP#T�.D:"K(z�&@�KPA�8 \"�rNrE(91�DE"& xIt5;� 1�;>;0(9?���"*D

P�*���K(3��� �&@+(8DE�*#T'K13"0�SDv :"&# # �*�`r:"& x�$�w�1*#w@{�$�T��%K�!"�"����0t�;�T1*;!� \(9#/�"`���"&t���DE"`r:#w@1�D�@+(8DE�5�9@ :�w��%�Dv;��1S'019# �*�3D�;&@{\19"&�EDE�LDv@jDE�w��%

(o�"*DE���3DE�T(3#�19"&��r:"9@�+���8 �q.f|;0�� R�m� u(9#/�"-�T��19"&�R� ED:���+1�'��T�����*r:�T���LD�� "&�u"&r>�!���{EDv E@(9#�1�'�13# �C�+;�(jR�m(S��)�K(9�&'-th"0�!�*�

�E�*��A�819��(9# #w'�'"9@���%�� Cth"&�!����C;�(S?�)(*��(S�"&?&@A#�(�DE"& E'�1*'�13# �«t��LDE;�(�;"& ��!"&��o� �"�rE� # �«t�;�� 1S;�� o���TrEr:�� x���3D�rE :"&� Dv;�

"&?&@#T(8DE"& �'K1�'1*# � �TU+l ��q

���u(&�3@+# D�5%���+���8 5�&� rEr��8 R����13�*��/�~13"9%���LD��w?�Kr�@��1�D�� "&���T��%�;(*?�zPA�*���~��cjD����$��T?�*#T'u R��?� ��th�*� �TU �j�Ed����q$yh#LDv;"9@%$;u�"

R�w��%# �`ED�@�&'�;�(j�(9�j� �9@(�DE�*#T'����*r:�T�+�*�K%����$�8 .���Tr�r:�� x�7�19�6��A1*"9��13#w@{7� "&��rE :"&�¡�`@{#LDE�w�A# �hED�@+��� �*Yx@�%�%�*ED�D�;�(8D\rE���K(j#2�3��A"9�

(*?�� :(S%��6��R13"& :�z;�T%$;�8 ."0�e?+�8 vP(3#�(*P�T# �LDE� �37�+�"*DE(SP#w'^"0�VDE(&��bDp;0(�D\ :� �9@�T R�� :(S��T�!(31*19�67bDv"!(9���K@{7�h"$rN��;+"&�"�# "0%0�21*(3#G(S��

R���K(3�3D��T1~�T��r�"j ��K(8DE�2"&� �T�O# "&��%�TD��8 ����!�S�!"& :'�|� �"��9@1�D�� "&�a(*�+�a13"0�K� :��;���7� "&�O"jr`13"0�K�# ��ca�+ :"���*�\(*�+�a(3# 7"a"&�OrE�T��

�!"*D:"& ���� #2#/7����� :13�7�jD�@+(3#b��A�*�*�u(S��u(3191�@ :(91�'GqA_a(9#��*���"0�~(*?�� :(S%�*�NR13"& R�K;��T%$;�8 z�T����(�DE�T(3#N(S�� �3@+(*�3DE�LDE(8Dv�T?�K(*P+� #T� D�� �*��

�"*DE(*P+#�'a"0�^DE(&��5D�;�(8D5 �� �3@A�T :�`DE :(S�$�rE"j ��K(8DE�2"&�`�T�m?� �@A"�E��(�DE�T(3#|th"& E��T�$%m�!���!"j �'�|�!"*D:"& hx�0�2# # `�T��?"�#/?�*�m�T�m(3�T�!�T�$%$�

��(�DE�T"0�TD����`�{"& :(9#K :�*��A"&����T�&%�`(*�+��r:#w@�2�� x��(j�"&��T��%Gq���?+�8 �(3#T# �`t�;�2# �)R13"& R�6o"&���!"�EDC13"&%&��LD��T?�mD:�*ED:oR;+"&t��"& ��K(3#

��� EDE ���P$@jDE�T"&�u�w�OPA"6Dv;)�!���)(*�+�Ot�"&�!���{�\D�;�Cr:���!(9# �m1�@{ v?��DE�����KDE"oPA�C;0�/%�;�� !(8DzD�;��C�!�8(9�)t��LDE;-��V(9# # �� eEDv(���&(3 :�

����?�T(8Dv� "&�h�p�&@ �DE"�R� R��q�fN;&@{zt�;+��#2�!�K(&# �*z�!"j R�>rE :� �9@{���3D�#T'C;0(S?�>;��T%�;�713"& :�*`"&�m13"9%���LD��T?��DE(&����AD�;+��'�(9 :�K(3# 7"~"0?�8 R�

:�7� :�*7���SD��*���T��D�;+��# "&tV��(SP�T# �LDE'����+��"&ra���?�� :(9#u��� EDE ��wP�@jDE�T"&���>�T��13#w@A���T�&%��!���jDv(3#� R�xDE(9 :�&(8Dv��"0�$�>(�D DE�7�SD��T"&����� 7"� :�$�8 R��

�&'R# ��c�T(&�GED�@&D DE�� :�w��%�A(S������*#T(*'�*�u��A�*�81S;Gq&HK"&th��?�� x�$D�;�`�*rEr:�*1�D:�(3#LD�;+"3@+%�;�13"&�R� ED����3D:#T'�r:"9@+����A(3 ����!"&���3vDZ�E��q d �b�`B����

(*���`(3 :�I�"*D� :��r:# ��1�D��*�h�T�Kr�@A#�#��ER1*(3# ������R13"& ��6*q

y�%�/��%V"&rAD�;���"& ��K(3#$P :(9���K� \(31*1*"&�K�+(*�� �*�zP�'K1*;�(*�$%�3\�T�`P :(9���!EDE v@1�D�@� :�*�0�!�xDE(SP"�# � ���(S��hr�@+��1�DE� "&�Ktz;0�21*;K�K(*'

���TrEr:�� \P'u��7c � d&U ��q ��?�� :(3#2#/��rE"& \P"*DE;u��7c{�*��{�"& :�K(3#�P :(9�w�e(*%+�T��%!;�(&.PA�*���e(&�R"&13�T(�DE�*�>th�LDE;�(K���81* R��(j7���T���!"*D:"& ���+�*�3�

(*���u�T��1* ��8(&��`�T�u R�8(91�DE� "&�!DE�T�!�K(&�th�*#T#�(j5(9#LDE�8 �(8DE�T"&�5�/�~���T?�� ���*��(�D DE���3D:�2"&��A?�� �@A"���(8Dv��(9#�(*���# ��(3 v��w��%u(*P� #2� Dv� �6Sq �Y�}Dp;{�

"*DE;�� |;0(9����AR���K(9�3D:�T1z�!�*�!"& �'!(3�+�!#T(*��%&@(S%��(SP�T# �LD:� �*.(S�����(3 �DE"K R���V(9�T�e ��*#T(8DE�T?+�*#T'eEDE(SP# ��"& \�K(3'���?���e�/�K� :"&?+���T�hDv;{�

(*P{����19�O"�ru"*D�;�� ��(�D�;"�# "0%0�2�3 � d�d��q5,�"9%��+� D��w?�o�{�� :r�"& E�K(3��19�)� m��*���-DE"��$�*13# �w��)"0?�8 �(3#T#Kt`� Dp;�(9%�O�T��P{"*Dv;�R�7c{�*��

;"&th��?+�8 R�|P�xDvth�*���{�p%������� `13"&�K�(9 :� R"&�}"�r�D�;�u7# "9�{��r�"j `(*%+�u"&� ��(31�;O13"&%&��LD��T?��r�@+�01�D�� "&�~D��*ED�(9r DE�8 `(3� ��@{EDv�!���3D�r�"j

�*�9@{1*(�DE�T"&��A����� ��67��*�>�!"�"�����(*����*EDE :"9%����@{7�h���T��th"0�e����\�T����T1*(�DE��Dv;0(�D|�!���e;�(9?��(!���%$��Tr:�T1*(9�SDv#T'^ED��*�7�{�� .���*1* :���!���&D

HA

L author manuscript inserm

-00243083, version 1

� ¿

th�LD�;e(S%��D�;�(S�et`"&�!���er�"j �DE"*DE(9#A x��1*(3#2#A(*��># "&��%�TD��8 ����!�S�!"j �'�+"&���T�K�e�*���T(�D:�5(*�+�!���*#T(9'�*�K?+�/x@(3#A R��1*(3# # �+(*�+�K1*(8DE��%"& �'

rE#w@{����1*' � d����q&f|;��67�� :�*�@A#LD:.(9 :�51*"&�K�(�DE�wP# �zth�LD�;e"*Dv;�8 .ED�@+�j�2�6�R;"0th�T��%hD�;�(�DNt�"&�!���� R�xDE(9�T�!(*�!(9�&?�(*�3DE(S%�h"0?�8 \�!�����T�

?�� EP(9#r�@���1�D�� "&�`th�*# #+�T�3D:"`"�# �`(*%+� � d�d��+d�l��q

_ � ��� � � ���� ������ ����� � � �� �������� � � �

���a�A�� :�T�!���"0�(*@{��6�I�!���!"& �' 1*;�(S��%�*!(S��a19"&��13���3DE �(8DE�T"&�O���Tr:rE� 1�@#LD�� �*!(9 :�u1*"0�!�!"&�#/' :�7�A"j �D:�*�o(*��� �;"& �D��TDE�8 ��

�!�*�!"& �'u# "����/�1*"&��� �$�8 R�*�!(K19"&�K�!"&�u13"0%���LDE�T?�`1*;�(S��%�`�3@+ :�T��%KDE;+�`�!���"9�(*@{�(3#Dv :(*�R�LDE�2"&��A(3#LD�;+"3@+%�;�(!�&�T x��1�D\13(S@{�(3#

#T�T���!t`� Dv;K;"& ��!"&��(3#A1S;0(S��%�3Z;0(&\�"*D�P{�*�����6EDv(*P# � �;+�*�!��d � ��q �h�� E'!r:��t�vD�@{�$� �6Z;�(3?+�Y(�D DE���K�jD��*��DE">"3P ����1�D:�/?�*#T'!�!��(jx@ :�

�@1�;�13"&%����LD��T?��1S;0(S��%�*IP'>���@+ x"9�{x'1*;�"�# "0%�T1*(3#D��*ED:��� :�7�"& �D:�"&r\�!���!"& :'�(*���!(�D DE���3D�� "9�0(&#����TrEr:�T1�@{#LDE�2�3.P+�*�T��%!P+(jR�*�>r:"&

D�;�}�!"0vD.�(9 �D�"9�=�@$P ���*1�DE�T?+�!��*# r� :�7�{"& �D�qA���~(>�"9��@A#T(8DE�T"&��2P(&��*�u1* �"����E7�*1�DE� "&��(3#\ED�@�&'m"�r5���&WCt�"&�!���m(3%+�*�~d&WuDE"~�$�

'��(3 x7�&��"K��T%&��Tr�� 1*(*�3DN�&�Tr:r��8 R����13�5�T�!�7�A�/7"��&� 15?+�8 vP(3#+�!����"j v'}��(&�7�6�7�*�zP'Kth"& ��K#�� ED|# ��(3 E���T�$%0��t�(&."9P{7�8 v?�*�K�9@ :�/��%�Dv;�

�!���"&�(S@{R(9#jDE E(S�R�LDE� "&�K"& N�T��D�;��'��(3 x\�/�K�!�*���T(8D��8#T'K(3r D��� �� d�X��q�����D�;��"*Dv;�� �;�(*����0th"&�!���!tz;"�PA��%�(*�`Hh4�fo�9@ :�w�&%�Dp;{�

�!���"&�(S@{R(9#�D� �(*�R�LDE� "0�K;0(9�`P{�RD D��8 \�!���!"& �'eR1*"& R�6����T�!���*���T(8DE�5 R��1*(3# #T�GD�;�(9�Kth"&�!����t�;+"`P��%�(3���6vDE :"9%���!(9r D:�� kDp;0�5r��T��(3#

�!���{EDE v@(3#$��� :� "$�`t�;� 1�;!19"3@A# �K�T�+�j�21*(8DE�\DE;�(8DADp;�8 R���!�T%�;3D|P�5(�1* �� Dv��1*(9#Ath�/�0�$"&t��9@ ��T�&%!t�;�T1S;hHh4�fo�h@{vD�P{�5�T��LDE�T(�DE�*��DE"

� :"*DE��1�DI�!�*�!"& �'^(&�;�(j�P+�*���~ :�7�{"& �D:���>P'u45�6���T1*�C�xD.(9#:q+rE"& .?� �@(9#��!���!"& �' � �$��.(9����b(*��$�N�xDI(3#Eq+rE"j �y�� � ��� �8q�f|;�

(*P{����19�m"&rK(m� ����!���"&�(S@{R(3#519"&�h�+(3 :� R"0�)%� :"9@��{��(*�+�aD�;���{"�����PA� #T�LDE'aDv;�(8D`th"0�!���-th�LDv;)�!���!"� v'-13"&�`�A#�(9�T�3D:��K(*'

� :��r:�� R���3DE�T(3# #T'�P{�`� ��671* :�wPA�*��Hh4�fZ��1*"9@#2�u;�(*?+�!# �T�!�LD��*�eDp;0� `ED�@A�9'�q�fb"C�&(8DE�*��"&�#/'�"&�+�`�{"9��@#T(�DE� "&��2P(&��*�u#2"&��%�LD�@�$�T��(3#

ED�@�9' � �&W �I;�(j5rE"�#2#�"0th�*�!D�;�K1*"0%���LD:�w?�z�A�8 �r:"& ��V(S�13�K"&r.t`"&�!���~(jID�;�7'e�+ :"&%� R�67.D�;� :"9@+%�;!D�;�`�!���"&�+(*@{R(9#ADE E(*�R�LDE� "0��q

FG �"3%� ��6�7�T"&�~rE �"&� � :���!���+"&�(*@AR�YD�">�{�� :�/�!���"&�(S@{R�5DE;� :"9@+%�;u(K��(8Dp@ :(9#G�!���+"3�+(*@{R(9#ADE :(S�$�� Dv��"0�$�kt�(&��"*D.(&�R"&13�T(8Dv�*�u�T�

D�;�� hEDp@�&'~"&r �&����t`"&�!���~t`� Dv;u(eR�/%���Tr:�T1*(9�3D�����13#2�T��K�T�ut`"j ����T��%C�!���!"& �'�"& .�+�8 �13�7�jD�@(9#�x�{�*�*����(9# Dp;"9@%�;C���Tr:rE� 1S@#LDE� �*

th�� x�«"3PA��� E?�*��(8D>D�;�O#T(8D��a�A�� :�T�!���"0�(*@{�(3#K(*�����A"�EDE�!���+"&�(*@AR(3#`��;�(&R�6Sq5fN;�� aEDp@{�9'�t�(&��z;"&th��?+�8 R�`# �T�!�LD:�*��P+'

@���13�� �DE(9�w�SDv' (&`DE"~D�;+�u(31�D�@+(3#bDv�T�!�T��%)"&rYDv;�!Dv :(*�R�LDE�2"&� (S��~D�;+�u��(8Dp@ :�C"&rYDv;�u19"&%���LDE�T?+�u(j���6���!���jD�g\"&�+#T'�D�t`"aP+ :�T�*r

�!�8(&�@ R�*`"jr519"&%���LDE�T?+�K�A�8 �r:"& ��V(S�019��th�� R�K@{R�*����th�LDE;+"3@�D5(*�&'a��?�(3#w@(�DE�T"&�a"&r5?�� EP(9#\�!���!"& :'a�TD�;��19"3%$��LD:�w?��r�@+�1�DE� "&�

�!"�ED�#T�T��*#/'^D�"uPA�!(9#LD:�� :�*�m�9@A�hD�"m�6EDv :"&%���a�$���A# �RDE� "&��:�|(���Ct��LDE;+"3@&D.DE(*���T��%a�/�SDv"~(91*13"9@�3D5# ��(3 v��T�&%a�*rEr:�*1�D�K�E�*��{��13�T(9# #T'

%�T?����D�;�(8D�#2�8(9 E���T��%K�*rEr:�*1�D:|�!�/%�;3D����*1* :��(j7���9@ ��T��%�D�;���!���"9�(*@AR(3#&DE E(*�R�LDE�2"&����q

f|;0�>DE'&�A�~"�r`�!���+"&�(*@AR�utz;�T1*;)# ��(j��`DE"O��� EDE�/�1�DK�*EDE :"0%���)�����A# �RD:�2"&�O�V(9' (9# �"O���RD:�� ��!�T��!Dv'&�{�C"�r`13"&%$��LDE�T?�

�&'Rr�@+�01�D��T"&�Gq&fN;+���'��`�jD�"&�}I(j��"j19�T(8DE�*�}th�LDE;e�@+ E%�� 1*(3#��!���"9�(*@A��5(3 ����"��R�wP{#/'!�!"& R��7��?�� R�Y(&ND�;+�8 ���� .(z�!"j R�5(*P+ E@��jD

���7�{# �RD�� "&��"&r~�*EDE �"&%���m(S������+��"&%���"9@{=(*���& R"&%���uD�;�(S���w����(8Dp@ :(9#`�!���"9�(*@{��6�zt�;+�8 R�mDE;+�)"&?�(3 ����*m19"&�3DE�T��@+��D�"

� :"&�9@19�Y��V(&# #+(*�!"9@+�SD�\"jr|�6EDv :"&%���Gq&,."&�`�(9 :�*�5D:"zth"&�����Kth�LD�;K��(8D�@ �(3#$�!���"9�(*@AR�6�0th"&�!���>th�LD�;!�@ E%+��1*(9#+�!���"$�(*@{��

HA

L author manuscript inserm

-00243083, version 1

� Ã

(3 ���(8D�%� ��8(�DE�8 | :� ��Kr:"& N1*(3 ��&��"0?0(&R1�@#T(3 |��� R"& x�$�8 R��"�EDE�*"9�A"& :"�R� ��$(*��K���7� R�*�R� "&�!�E7�*�Yr�"& N :�7?� ��t � ��� �E��q8��"0�!���!t�;"`;�(S?{�

@������ E%+"&��5"�"9�;+"j ��*1�DE"&�K'>;0(S?��(9# �"zP{�*���!�;"0t���D�"z;0(9?�5# "0th�8 \R1*"& x�*\"&�!�"0�!���+"0vD:�E"9�A�8 �(8DE�w?���!�*(jx@ :�*."&r�13"&%$��LDE�T?�

r�@���1�D:�2"&���T��%�s¨ �l¤��G?��� EP(9#N�;"& �D:�TDv�8 �� �!���!"� �'��#�"0��%�TD:�� �� �!�*�!"& �'^(S���# "&%�T1*(9#k ��8(&R"&��/��%�Atz;�8 R��(j��+(8DE�T���3D:�t�;+"�;�(3��(

;�'ED��8 ��*1�DE"&�K'��P$@jD5t�;+"07��"&?�(3 �� �6zt`�8 R�! R�RDE(3�/��*���b�;+"&th�*�mEDE(*P+� #T� Dv'a�T�m13"&%$�0�LD��T?�}�{�� :r�"j ��K(*��13� � �&U���q<K(S��T¤@§.³ ¬ �\(3# R"

:�7�"& �D��*��D�;�(�D�x@ E%��T1*(3#o�!���"9�(S@{�� (3rEr:��1�D��*����A�819�Tr:�T13(9#�#/' �;"& �D:�TDE�� :� ?�� EP(9#o�!���!"j �'s�!"& R��D�;�(9����;�'7� "&# "&%�T1*(&#

�!���"&�(S@{R����t��LDv;K�"V7�w%���Tr:�T1*(9�3D����Tr:r��8 R����13�5"&�K(8D Dv���SD�� "&�!(S�����{�'�1*;"0�!"6D�"& GDE(&��R�:�&t`� Dv;`�{�� :rE"& ��V(9��13�*\13"& � :�*#T(8DE�/��%KP"*DE;

DE"�D�;�!(S%�!(�D.D�;�`DE�T�!�u"&r5"&?�(3 �� �81�D�"&�K'm(*���D�"eD�;+�!'+�8(9 xKR�w��13���@ E%+�8 �'Ai�;�T%�;+�8 h�1*"j R�*zP�*�T��%m :�*#T(�DE�*�eDv"m"�# ���� �(�%�>(8D

�@ v%0�� E' � ��d��qA,."&��19���SDv :(8Dv��"0�~(*���(�D DE���3DE� "&�C���Tr:rE� 1�@#LD�� �*5;�(*?+�K(3# �">PA�*���~ :�7�A"j �DE�*�ur�"j I@�����(8Dp@ E(3#��!���+"3�+(*@{7�K�w�~th"0�!�*�

DE :��(8Dv�*��th�LD�;�(9� ��@?�(*�3D�1*(3��19�8 C1*;���!"9D�;�� :(*�$'$�`(9#LD�;"9@%$;-DE :��(8Dv�!���3Du(3# 7"��T���9@A13�*��;+"6D�r:#w@{�;+�3mtz;0�21*;��K(9'�(3#��"�P{�

(j��"j1*�T(�DE�*�`th�LD�;!�@1*;K���TrEr:�T1�@A#LD:� �* � �����q

y �� � � � � �� � ��� ������ ����� � �� � ��� � ���� � � �� �

y�DC# �8(&ED)����� "&r��{�� xR"0�$o"&?+�8 m��d�'+�8(9 xm"$# ��(*���d$�� "�r!D�;"�7�)"&?�� �jd ;0(S?�-7"&�!�)r�"j �� "&rC1*"&%���LD��w?{�

�T�`�(3�T ��!���3DN :(S��%��T��%�rE :"&���!�2# �!���*r��T13�LD:NDv"!�����!���jD��T( � �$l��q9y���13"0�$vDE�LD�@jD��6|DE;���!"0vDNrE R� �9@{���3DNr�"& :�¡"jr\�����!���jD��T(�tz;�T1*;

(31*1*"9@+�SD�5rE"& �(*P+"3@&D�l����s"&r.(9# #N�����!���3D���(&���rE"�#T# "&th�*�>P+'~MN��t�'C]�"��9'~���������3D:�T(e��W+�����:��?�(jR1�@#T(9 ������!���3D���(����8d�����(*���

�����!���jD��T(h"&r�DE;�5F�(3 E���T�7"&�hDv'j�A���Ed�^��q&FG :��?�(9# ����13�`"jr\y���� .(9 :"9@�+�KU�¬�T��1* x��(j��T��%e#2"&%��/vD:�T1*(3#2#T'!rE R"&��W� (8DN(S%�h��dzDE"

:��(31�;�(*��(j�'$�K�jD:"*D��)(8D �j��'�8(9 x=th�LDv;�(*�¡�6ED��T�K(8D��*��� :��?�(3#2���13��"�rCW��� � � � ��q�f|;0� �"9�{� � (S@{�R�T(*���T��1* R�*(j��-�T�

� :�7?�(3# ���+13�Yx@%�%+�6ED��D�;�(8D�y���� |�"*DNR�T�K�#T'K(5�"& ��K(3#+�T��?"�#w@jDv� "&��(3#$� :"&19�6�7�&P�@&DAD�;�(8D�P�T"&# "&%�� 1*(9#rE(91�DE"& x\"*D�;�� GD�;�(9��Dp;"���

�T�`�{# �T1*(�D:���!�T�KP+ :(3�w�!(S%�*�T��%!(9 :�5�T��?"&#T?+�*�{q&_O"& :�*"0?�8 R�+(*%��3�� :�*#T(�DE�*�K1*;�(*�$%�6��T�hDp;��� R��?0(9# ����13��1�@+ E?�5(3 ��5�"*DGDp;��R(*�!�`�T�

�!���u(3�+�!t`"&�!���Gqj��"&�!���~(9 :�`"&?�� :(9#�#��!"j R�`(8D\ :� ��u"&r��$��?�*# "9�{�/��%u�����!���jD���(`D�;�(*�u�!�����(*���KD�;�z� R��?�(3# ����19�K"jrIy����

;�T%&;�� 5�T��th"&�!���eDv;�(*�u�T�u�!���~(9r DE�� bD�;�`(9%�K"&r���d��El��e'�8(9 x���P�'uW�E�$��rE"�# �Aq+fN;�� �%����$�8 5�&� rEr:�� R����13�z�{�� xR� ED����?���C(3r DE��

1*"& : :��1�D��T��%mr:"& ��&�Tr:r:�� R���+13�*`�T�a#T� r:���7c��{��1�DE(S�1*'�� ��X��El�� ��qGf|;��!�!��Dv(j��(*��(9#�'7� z�{�� :rE"& ��!�*�uP+' � (3"�¤@§.³ ¬ � � l&W �� :�7�"& �DE�*�C(

R�w%���Tr:�T1*(9�3DE#T'>;�T%�;�� \�T��13� ������19�h"&r|y ���T�>th"&�!����13"&�`�(& :�*��DE"}�!���{�+13"& � :��1�DE�T��%!r�"j \�T�1* ��8(&��*�Kr����V(&# �z# "&��%��?+� Dp'^� ��4

�3qLd��&��q|�N�&#�(S��"¤@§�³ ¬ � � l$��`;�(3?+�~�@+%�%�*ED:�*�mD�;�(�DV7�7c-���Tr:r��8 ����019�m�T�Oy����T��19� ������13�C13"9@A# �mPA�~ R��#T(8D��*�~D�"a%+�*"&%� :(*�$;�T1*(3#

���TrEr:�� R���019�3�i�(5;��w%�;�� N�T��13�2������13��r�"& �th"&�!���`P{�*�/��%V"9P{7�� :?+�*�h�T�K��@ �"9�{��(*�K(*��`yhR�T(S�h�A"9��@#T(8DE�2"&���&P$@jD���"6D��w��D�;� �KB�q

���!(*%+�6�� R�*#T(8DE�*�`�+��@ :"��$��%����� :(8Dv�T?�.�+ :"�19�6�7�*.�@1*;!(&|y��K�3D�;+�Y��(3 �# � �*ED� R���+"j �D:�*�K�'��h�&D:"&�¡�/\19"&�!�!"0�#T'!�T��(*P+� # �LD�'

DE"�# ��(3 v��(*��� ��*1*(3# #^���t �/�0r�"& :�K(8Dv��"0��r:"�#T# "0th�*��P+'�(�� �"9%0 R�*�R�T?+��# "��«"&r "*D�;+�8 O13"0%j�+� D��T?��(*P+� # �LDE� �3*qVyID2DE���jDE�T"&��

1*"&�19���SDv :(8Dv��"9�)(*�+� 7"&�!�C?�� EP+(3#�R��� #2#/��2�"*DE(*P#/')th"& :����r:�/��&�T��%��K(3 ��~(9#/7"O(3rEr��81�D��*�O(8DK(S� ��(3 �#w'«vDE(*%�Ctz;�8 R��(j>�K( ��"&

��(�DE�T(3#G�&� 7"j �� ���3DE(8Dv��"0�$����� :�2"3@A�#T(S��%&@(*%�`��� R"& R���� x5��(*P{����3D\rE :"&�¡�"& ��V(9#G(S%�w��%�:�A(S�� :(*c+��(`(*���>(*%&�"���T(`@{x@(3#T#w'u"j191�@ .(�D

HA

L author manuscript inserm

-00243083, version 1

� Å

(�#T(8DE�� bED�(S%0� � l&U ��q9fN;+�8 ��Y� .R"0�!�Y#2�T�!�LD:�*�K��?�2������13�bD�"K�@%$%�6vDAD�;�(8DAD�;�I�(8D2DE�8 v�V"&r�13"0%���LDE�T?�5# "��\� |�"*DAD�;+�YR(9�!�5�T�K�!���

(*���Kt`"&�!����+(*���Dv;�(8D�t`"&�!���!;�(*?+�Y(9���8(9 :#T� �� b"&�7�xD|(*��>rE(jEDv�8 |� :"9%� :�*�7�T"&�e�E��*�zr:"& b ���?+� ��t �TW �E��q���@ :�w��%hDv;�513"9@ RR��"&r

y��h�+th"0�!���hD:�����D�"!�;"0t�%� R�8(�DE�8 \�T�`�(&�T E�!���3D:��T�!#T(9��%&@(*%����+� #T#/7�A�*��{��13�T(9# #T'!��(9�K�T��%!(*�+�Kth"& :�K R��13"&%$�0�LD�� "&��+���*# (S'�*�

:��1*(3# # �\R���K(3�3D��T1��!�*�!"& �'�N(S�0�C�+"07��wP#T'm(3# 7"C?�� EP(9#br�#�@A���1S' � l�d$�El�l��q�].(*'# �*�¤@§.³ ¬ �brE"9@��+�C�"�7�T%���� rE�21*(*�3D��&� rEr��* :����13�

P�RDEth�*���!Dv;�z�{�� :rE"& ��V(S�13�KR19"j ��6�"�r\�V(&# �`(*�+�er����V(&# �`R@�P����81�D��th�LDE;�y��h��"&�#/'e R���A"& �DE�w��%u ��*#�(�DE�T?�*#/'^��V(&#T#N��r:r:��1�D�R�T�9�3

"&r�%������� x�0t��LDE;Kr:���K(3# �I�(8Dv� ���3D:\"9@jD��A�8 �r:"& E�!�T�$%K�V(9# �6I"&�!#T(*�&%&@(9%�bDv�6ED� � l � ��q

� �� � ��� �� � � ����� ��������� � ��� ������ � � � � � �� ��� � ��� � � � g � ����� ��� � � �� � �� �

f|;0�z�K(3 ���*�!1S'1*# � 1`r:#w@1�Dp@(8DE�T"&�5�/�^�*EDE �"&%���u(*�+�K� �"&%�*:DE�� :"0��YDp;0(�D."&1*1�@ .(jI�(9 D\"jr�Dv;�� R���+ :"��9@1�D��w?�h1S'1*# �*��"j

�9@{��D�"!"*Dv;�� ��7cjDE :�w�7��1`1*(*@A��*��A(S�����(3 �DE"K�+#�(S'e(S�^�/�h�A"& �DE(S�SD\ �"j#2�h�w�u����;�(9�019�T��%u�@{R19���jDv��PA�T# �LDE'KDE"!19"&%���LDE�/?�h�0'$�r�@�1�Dv� "&�

"& m��7@ :"$# "&%�� 1*(3#���� 7"& :���� x�>(j=th��# #�(j«�@�P{�DE(S�SDv��(9#T#T'��T�rE#w@{����19�T��%�13#T�T��T1*(9#e19"9@ x7�-(S��� �'��`�jD�"&� 7��?�� :�LDv'�q>B+���!�2#�(9

�'��`�jD�"&�} (3 :�« x�7�A"j �DE�*��P+'�th"&�!����19"&�`�{#T(3�/��T��%�"&rm� ����!���EDE E@+(3#ex'���& :"&�!�3�V� R���!���EDE E@+(3#��&'���;"& ���1��&�/7"& :���� x�

�"�ED��(9 �D�@$������� ��67��T"&�a"& 5�A"�ED��(9 �D2@����AR'�1*;+"07� ��|(*���eDv;�}�{�� R�T�!���"9�(*@AR(3#�DE :(S�R�LDE� "&�m(*��C�!���+"&�(*@A��9iN(3#T#."�r5tz;�T1*;

"&131�@ N(�DG(��V"&�!���&D�t�;���!�*EDE �"&%���!# ��?+�*#A���81* R��(j7�6\(S��� E"� �t5;����Dv;�8 R���/\(z :�*#T(8DE�w?�5"& N(SP{R"&#w@jD:�5#T(31��!"&r�� �"&%�*ED:�� R"&��5"&

� :"9%�*ED��T���$(3#LD�;�"9@%�;K�+"h19"j � :��#T(8DE� "0�K;0(&|P�*���!�����!"&�AEDE :(�Dv�*�`th�LD�;}7�� :� 15# ��?�*# *q9f|;�67�Y�'��`�jD�"&�}Z�"*DE(*P+#T'V�/�1*#w@{�����!"�"+�

�th�T�&%O(S���(����81* R��(j7�8��7������"�rCth�*# # �2PA�*�T��%�K�T � :�LDE(*P+��#2� Dv'�K(S�jcA� �RDE'�}�!���!"& �'�(9���19"&%���LDE�/?���&'Rr�@��1�Dv� "&�Gq�f|;�*��

��� R"& R���8 R�(j�R"&1*�T(8D��*�>th�LDE;� R��� �"��9@1�DE�T?+�3��1*'�13# �5DE �(*�R�LDE� "&�A��/�et`"&�!���u(3 R�h"&r D����u13# "�7�8#T'u ��*#�(�D:���+iGt`"&�!���uth�LD�;u(`;��vDE"& E'

"&r\�!"�"����&�/7"& :���� .(j7R"&1*��(�D:�*�}th�LDE;� :�7� :"$�3@+1�DE�T?�`��?���3D:5�3¤�� Â����0 ����!���EDE E@+(3#G(S���K��@�� E�A�� :�w@� �&� �"& :�$�8 RR�b(S�����(3 NDE"`;�(S?{�

(*�!�T��1* ��8(&��*�K ��/x�e"&rb�$��� ��67�� "0�!(8D��+�8 ��T�!���"9�(*@AR���E��*��r�"& b ���?�2��tz � l�X�� �G� �:��q*���LD�;! R�7%0(9 :��DE">���7� R�6��� "&��+(��!"&���9#+;�(j

D�;&@{^P��%&@� Dv"-�����8 �%�=t�;�� 1*;-19"&��13�7�jD�@(9# �T�3�*!Dv;�CP �(3�w���6EDv :"&%�����!�T��/�h@+� 7�xD}�"��/�SD>�T��t�"&�!����(&u(O1*"9�3D:�/�j@$@�

EDE(* �DE�w�j%>th�LD�;K(5� R���!���EDE E@+(3#A�'���& :"0�!���T�hD�;�5W�$���(S���!����13"&�K�+(j�R�w��%K�+"0vD��(3 �D�@������7� R�67R� "&�!�T��Dv;��������$rE"�# #T"&th�9��P+'

D�;��1*'�13# �T1��'��h�&D:"&�e\"$r{Dp;�.�A�8 R�T�!���+"3�+(*@{R(9#U+��\(*���K������/�j%Kt`� Dv;�D�;�5�!���"9�(S@{7�Y�'��+�j �"&�!���LD:7�*#Tr�q3f|;��/|;$'j�A"*DE;+�3R� \"�r

(�1*"9�3DE�T�&@�@+� "&r�?&@#/��8 �(*P�2#��LDv'h;�(&\ :��13�*�T?�*�`# �LD DE#2��(8D2DE���3D:� "0�V�T�K :�*#T(�DE� "9��D�"`1*"&%���LDE�T?+�Y�$�/�"j R���� xSq

½B¦�±H¶>¯�¯³R£[ÁG�|(3�9@#LD5rE���K(j#2�65D������DE"u�A�� :r:"& v��PA�xD D��� �"&�~DE(&��`"jr�?�� EP+(3#\�!���!"& �'�(S��~r��T��>�!"*D:"& �19"&"j R�&�T��(8Dv� "&�

1*"&�K�(9 :�*�hD�">�V(&# �*���t�;�� R�8(&��K(3# �3I�A�8 �r:"& ���P{�RD D��8 �"&����� :13�7�jD�@+(3# �E��(�DE�T(3#Dv(j��*q0HV"&t`��?�8 R��t�;�����?�� ��*EDE �"&%���~#2��?�*#

�T��th"&�!���~(9 :�`���*1* :��(j7�*����t�;�RDE;�� ��9@ ��w��%ur:�RDE(3#�# �Tr:�!�� ��*# (8Dv�8�KDE"�%+����xD��T1!�&� �"& ����8 RR�:��"& ��9@ :�w��%!D�;+�`�!���{EDE v@(3#���;�(j��6��"&

(3r DE�� �D�;�5�!���"0�(*@{��6�&Dv;��/Z�(8D2DE�8 ��>�V(9'KPA���T��?�� x��*�iA# "0t�# ��?�*# �"&rb�3vDE :"9%����rE(*?"9@ ��T��%hDv'j�+� 1*(3# #/'!�K(3# �h���� # # .(S��KP+�*�T��%

���RDE :�T�!���&DE(3#+D:"`DE'&�A��1*(9# #T'�r:���!(3#2�V��� #T# *qAB$@1*;�(`�(8D2DE�8 v�u�K(3'>P{�` R��?�� xR�*���A(�D.# ��(jED|�(9 �DE#w'u"& NDE���K�A"j �(3#T#T'�+P+'u��cA"&%���+"3@A

HA

L author manuscript inserm

-00243083, version 1

� �

(3�&�!�/�0� EDv :(8Dv��"0��"&r5�6vDE :"&%+���~t�;+��1S;�1*"9@A# ���!"��9@{#T(8D��K13"0%���LDE�T?�>r�@��1�DE�2"&����"*DE(*P+#T'~?+�8 vP(3#|�!���!"& :'a�E�7cA���K�# �Tr:� �*��P�'eDp;{�

�*rEr:�*1�D:^"�rK�N4�f¡"&�)%+�� �# �th�LDv;)fN@ v���8 �B'&��& R"&�!�*�5"�r�Dv;�m13"0�SDv :(31*�7�jDE�/?�C�{�T# #z"&�-��"&�A���!���"9�(S@{R(3#�th"&�!����5(*�+��Dv;�

�"��R�wPA# �a(9# Dp;"9@%�;�13"0�SDv :"&?�� x���(9# ����r:r��81�D:C"$re�|4�f "9�-�!���+"&�(*@AR(3#zt�"&�!���{�`R�*�mPA�*# "&th��qIHh����13�*�z� D�� C�T��1* R��(jR�w��%#2'

��?� �����3D:�`(�Du# ��(jvDurE"& ��"&�!�)t`"&�!����PA� "�# "9%�21*(3#T#T'�?&@A#T��� :(SP# �mD:" �"& ��V(9#K1*;�(*��%+�6o�T�� R�7� :"��9@1�D��T?� ;"& :�!"0��67�5D�;�(8D

t�;�����?+�8 zP :(9�w�a�6EDv :"&%���O# ��?�*# `rE(&#T#\P{�*# "0t Dv;���!�T�+�T�K@�¬P :(9�w� �*EDE :"0%���� R� �9@�T R���!���jD:�|r:"& zt�;�(8DE��?�� � ��8(&�"9� (S���m(8D

t�;�(8DE��?+�8 N(S%�*�&P E(9�w�V�&'Rr�@+�1�DE�2"&�K�V(S'!����@{�*�$# �8(9���T��%�DE"z?�(3 :�T"9@{|���@+ :"��2�{�'01S;�T(8DE ��T1Y�&� 7"j ����� x*q

�����HG��T�=6=NT8;?=6.DP&.K�6.*9L�6.?�,POQ8;7>7R8J-�(;6.*=&T,�?�C�-�6=N.?�4�(;456.?

��(3 ���"9@{>19#��/��T1*(3#YvD�@��� �*};�(3?+�u�T��?�*ED��T%�(8DE�*�uDv;�C�8r�r:��1�D:>"&rK��cA"&%���"9@{>�*EDE �"&%���>"j K�@�PAEDE�LD�@jDE�/?�!DE ��8(�DE�!���3D`"��

1*"&%���LDE�/?�ar�@��+1�DE� "&��5(&�th��# #�(&u"0� D�;�m ��/��-(S��)13"9@ RR�a"&r������!���jD��T(q._o"�ED!�7�� �$���!� "�# "&%+��1*(9#hED�@A�&� �*C"jr>;"& v�!"&��(j#

�T�3D:�� E?+���SD�� "9�C;0(S?�Kr:"&1�@{7�*�u"&�!Dv;�K�!���+"3�+(*@{7�`t�;���u;+"� E�!"&��(9#N���7� :�T?�(�DE� "&�~� .Dv;�`�!"vD.�& :(9�V(�DE�T1K(*������*r:�T���LD��T?�3��(*��

�9@ :�T�$%ht�;+��1S;}�"&�!�5th"&�!���K(*�$�{��(3 ���(* �DE�T1�@#T(3 :#w'`?&@{#T�+�8 �(*P# �\DE"z;�8(&#LDv;V1�;�(*�$%�3*q

��� ������ �� � � � �� � � ����� ��� Hh4.f

4�"&�9���jPA�� E%u�xD|(3#Eq&;�(S?�� R��?�� ��th�*�hDv;�z?�(3 :�T"9@{ZHh4�fOrE"& ��K@#T(8DE�T"&�.(9���Dv;�*�T |@{R�`�T�!��@ �"3�A��19"&�h�+(3 :�*�`DE"hDp;� �KqwBkq

���3W ��q$y��K@1S;~#T(3 v%�8 �1*;"&� 19�K"�r\� �"��9@1�D:5(S���(3�&�!�T�+�/vDE :(�DE�T"&�u�!"����3�1*;�(3 �(31�DE�� :�T�3�*.Dv;�`��@ :"9�A�8(9�~�/�^19"&�K�(9 :� R"&�ut`� Dv;

D�;� �`B!�K(3 v��RD�q3��@ :"9�A�8(9�Kth"&�!���>�V(9'`@{7�Y(�?0(9 :� �RD�'�"jr|�6EDv :"&%�����$tz;�8 R��(j\�T��Dv;� �hBA��(SP"9@jDNX���� "&rG�A"�EDv�!���"&�A(*@{�(3#

th"&�!���o@{���"& :(9#.1*"&� ��@+%0(�DE�*�a� �9@A�w��u�3EDE �"9%���{!�E,I�N�N�:��t�;�T1*;o�V(9�T�#T'a19"&�3DE(3�w�O�6EDv :"&��u�@+# rE(8DE�u��W�=�!�RDE(*P+"�# �LD:�*};�(*?�

P�*���- R�7�{"& �Dv�*�)r:"& �FG ����V(9 :�w���"&�+�a"&rhDv;�m�!"+ED!rE �� �9@{���3DE#T'«@{��*��,.�N�N��q�B�'ED����!��1O�3EDv :"9%���{��K(*')PA�m%+�T?����"j �(3#T#T'�

DE E(*�R�$�8 ��K(3# #T'�����3DE �(3���� ��V(9# #T'�$?�(9%0�/�0(9# #T'�A"& |P�'e�/� ���*1�DE� "0�kq9y���(j�(3#G�� �(*'!� .(9# �"}�"&t�(S?�(3� #T(*P+# ���T����@ :"9�A�8(S�e19"3@+�jDE ��T�6*q

���~��@ �"9�{�*������ ��V(9#G�+(8D�;�t�(9'�� ��*��"&�!�T��(8D��K�T�!Dv;��B"9@jDv;���[G �(*��1*�*�G� Dv(3#T'�|B��(9�w��.t�;+�8 R��(jz"j �(3#�rE"& ��h@A#T(8DE� "0�$Y� :��?(9�T#N�T�

y���%#2"0��B+(*c"9��13"9@��3DE :�2�6*q5f|;�)"$# ���� ~��@+ :"9���(3���+ :"��9@1�DRm1*"&�3DE(9�T��*���6EDv :(3�&� "$#K?�(3# �� :(�DE�*�`(*���)DE;+�O�!"& x�O R��13���3DC"&��*

�!� 1* :"0��T�3�*����lβ

�v�6EDv :(3�&� "&#EqNf|;�*��^� :"��9@A1�D:>(3 ��u�!"& :��th� �$�*#T'a��@$P# �T13�T�3�*�O(S��m@{7�*�O�T� ��@ :"9�A�8(S� 19"9@�3DE �� �6`D�;+(*��Dp;{�

,.�N�\�+t5;�T1*;�(3 :�z(3# �">(*?�(3�T#T(*P+# �h�/�e��@ �"9�{�&q��v�VDv;� �Kq �!qL�A,.�|�a�+ :����"&�!�T��(8D��h��(&��w�KDE;� �KqwBkq �Ntz;�8 R��(j>�8lβ

���*EDE �(3�&� "&#��

D�;�>�!"�ED�� ��6R1* ��wP{�*�C13"&�`�A"3@+��C�T�m[G :(S��1*�jq+����(*�a�*EDE �"&%������t�;�T1*;m��"C�"*D�� �"*DE�81�D5(S%�(3�T�ED5"�ED��*"9�"& x"�R� zP�@&D5 E�*# � ��?�

th"&�!���!rE �"&��19# �T�K(31�D��8 ���1��'��`�jD:"0�}��+�@1�;K(j\�*EDE ��T"�# �&th�* ��.?�� E'`�A"3�$@#T(3 �@��3DE�T#+ :�*19���SD�#w'!�T�!R"&�!����@ :"9�A�8(9�K1*"3@+�3DE :�2�6*q

f|;0�«1�@ : ����3Du19"&������@Aa� �D�;�(8D�t�"&�!����t�;"�;�(9?�O�+"3D�@��+���8 v%"&�� ;�'ED:�� R�81�D�"&�K'��;"9@{#T� P{�o� ��671* :�wPA�*��(*�

"9���{"�7�*�uDE :��(8Dv�!���3Dzth�LD�;a(&�����*�C� �"&%�*EDE(*%+����q�f|;�uR(9�!�u���/?�8 RR�LD�'a(j}r:"& `�6EDv :"&%���>� K(9#/7"mr:"9@+��mr:"& z� :"9%�*EDE(S%�����

t�;�T1*;C1*(*�uPA�K���T?�2���*�u�T�3D�"!D�;� :�*�!�@$P%� :"9@��A*g�Dv;�!,���WN�`���� :�T?�(�DE�T?�*�"$r.� �"3%+�6ED��� x"0��!���!�*�& R"9c'&� �"&%�*ED:�� :"0��K(319��DE(8DE� �

HA

L author manuscript inserm

-00243083, version 1

� �

_aF�yz�E���&'+�j �"&%�*ED��8 �"&��*�:��,����8X^���8 ��T?�(8DE�w?�3�"�r\�"& �D��6vDE"�ED:�� R"9��!���"& ��xDv;� ED��8 �"&����.(*�����(�D�@ :(9#�� :"9%�*ED��8 �"&��`(*��uR�T�!�2#�(9

1*"&�K�A"3@+���� ���3W ��q.��� Dv;� �VqwBA�5_aF�y � !Dv;�m�!"�ED}@{7�*�)�+ :"9%�*EDE(*%+��� �pt�;�T1*;�� ��!"0vDE#T')@{7�*���T�-13"0�KP{�w��(8DE�2"&�-t`� Dv;

FG ����V(9 :�w����qA�E�~��@ :"9�A�6���"& R�xD�;+�/vD:�� :"&�+�K(313�RDE(�D:�*����(8D�@+ :(3#��!� 1* �"&��T�3�*�^� :"&%+�6ED��� x"0��6���!�*�& R"&%�*EDE"&���1S'j�+ :"*D:�� :"0��!(913�RDE(8DE�*�

#T'���*EDE ����"�# ���"& E%+�6EDv x��# �C(*��¬�&'�& :"0%�6vD:�� R"&���(3 ���"&r D:��� @{7�*�Aq��E��[� :(*��19�6��� �"&%�*ED��8 �"&���"& ��LD:���(�D�@ :(9#m� R"&�!�� x�

�&'�& :"0%�6vD:�� :"&�+��(*��!�'��3Dv;�xD��T1h�$�8 R�w?�(8DE�T?+�65�2� ���%���(3�+�6�"& N�+"j v� :��%$�0(S��*��N(9 :��� R��r:�� : :�*�K(9��>�T� �Kq �!qL�&D�;��@{7�`"jr|(313�RDE(�D:�

"&r��"& ��xDv;� EDE�� R"&��*�\# ��?"&�"& v%�6vDE :�*#.(S��m_aF�y � :�*��"0�!�T��(8DE�**q�FG �"9%�6vDE(*%���}(3 :�>�!"�ED�#T'm%�T?+���a"j �(3#T#T'�|P�@jD�D� :(*�R�$�* E�K(3#

�'ED����}.�p�"& :�RDE;� ED��� :"&���(31*�RDE(8D��*��# ��?�"&�+"j v%�3EDE ��*#T�k(9 :��(3# R"z@{R�*�K�w��Dv;�zB1*(*�����/�0(S?�T(*�K13"9@+�SDv :� �**q

f\��P+"j#2"&��*�\(C;�'&P :� �=�!"�# �*1�@A# ��th�LD�;)�6EDv :"&%���+��13�|�+ :"&%�*ED�"&%����T1C(*��m(9���& R"&%����T1�� �"9�{�� �DE�2�3��\� !(9# R"m�A"9��@#T(3 `�T�

R"&�!����@ :"9�A�8(9�e1*"9@+�3DE :� �**q&f|;� \� �"��9@1�D|;�(jI�V(&�T��#T'>P{�*���K@A��*�`DE"! R��# � ��?�h�'��`�jD�"&�}�(S��!(S?"&� �>th�LD�;�& :(St�(9#+P{#2�*�3���T�&%Gq

� D:«(31�DE�T"&���/�� :�*#T(8Dv� "&��DE"¡"�ED��8"9�A"j �"��� � :��?���3D�� "&��;�(� P�*���� :�*19"&%&�� �9�*���T��7"&�!��19"9@��3DE :� �*���(S����LD:���rEr:�91�Da"&�

1*(3 ��j�T"&?�(&R1�@{#T(9 br�@���1�DE�2"&�!� �EDE�T# #A(K�@�P��x�*1�D|"&rN R�67�8(9 :1�;!(S�0�K�$��P(8DE�&q&4�(9#T"3c+� r:����*�$t�;�T1S;e� \�"*D|(h1*"9��?���3D�� "&��(3#+H`4�fmP$@jD�(

R�*# �*1�DE�/?�5�6EDv :"&%���K :��13���&DE"& N�!"&�9@{#T(�DE"& b��B�N4�_a�:�9;�(&|P�8���K(*?�(9��#T(SP# �5�T�K��@ :"9�A�YR�/�019�!�8X$X�X ���j���q

yh.(` :�*�@#LDN"&rGDp;� .;+�xD��8 �"&%����*�LDv'!(*���Dp;�5th� �$�Y(9 : E(S'!"jr�� :"&�9@1�D:I(*?�(3� #T(SP# �*�+��@ :"9��z#�(91��.#T(3 v%��# "9��%{�TD��� :��45,\f

t�;�T1*;>@{7��D�;�h�(3�!��� :"��9@1�D��(91* :"���1*"9@��3DE :�2�6\D�"e�*EDE�/�e(8Dv��D�;�� �� ��e(S��KPA����*rE�LD."&rNH`4�f)"9�!;+�8(&#LD�;u"9@jDE13"0�!�6����@1�;�(j

1*"&%���LDE�/?�Kr�@��1�D�� "&����{�'1�;+��(�DE :�T1!�'��`�jD:"0�V(�D:"&# "&%$'$��1*(9 :��� "0?0(&R1�@#T(3 ���� ���(j��6���(S���P ��8(&ED.1*(*��19�8 ���3W ��q+�v�}Dv;� �VqwB�q ��fN;��

��"&�!���{� .HK��(j#LD�;u�v�0�LD��T(8DE�w?�>BjD�@+�&'^�T��HK�RB�\�T��?+"�#T?��T��%KDE;�`r:"&# #2"&th�2@��~"&r �&�����>th"0�!���$��(9��hD�;+�Y��"&�!���{� ��v�SD��� E��(*DE�T"&��(3#

BjD�@+�3')"&r`# "&��% �5@ :(�DE�T"&� �z�*EDE :"9%���O(3r D��8 K_o���"9�(*@AR�~� � �RB����5_O�.W�W$U�Ct�"&�!����K�/��D�;� �Kq �!qL�\y5@{EDE �(3#T�T(m(*���~<}�*t

�b��(3#T(9����.�9@{��D�"mPA�~19"&�K�# ��D��*�O�T� W�$��do(3�+�aW���$�a R�*R�+�*1�DE�T?�*#T'�Ith�� R�~���*7�T%���*�mDE"o� �"&?�T���m�T��r:"& ��K(8DE� "0� (*P+"&@jD5D�;�

�*rEr:�*1�D:«"&rmHh4�fYq`f|;��FG ���?���3DE�T��%¡Fk"�EDv�!���"9�(S@{R(3#�_a���!"& �'�Mb"��«(*�+��y�# �S;�*�T�!�� x� ���� 7�8(&R��t`� Dv;�45�7�#T(j19���!���3D

�bEDE �"9%���hEDp@�&'���F�4��NF�y�4��-�w�eDp;� �KqwBkq �.t�� #2#b��A�819��r��T13(3#T#T'C(3���& :�*��D�;� �3@A�*EDE� "&�m"&r�t�;�RDE;�� 5�6vDE :"&%+���$z1*(*�m���*# (S'~"&

� :�7?���3D������!���jDE�T( ���3U ��q�f|;�5Hh4�fOt�;�T1S;^� z��?�(3#w@(8Dv�*�e�/�e(3#2#{Dp;�67�KED�@A�j�2�6���� 519"3�3D��T�&@{"9@{�"j �(3#�(3�&�!�T�+�/vDE :(�DE�T"3�u"�r�,I�N�

th�LD�;~"& .t`� Dp;"9@jD._aF�y!q�y�DNDp;���+ :�*����3DNDE�/�!�6��PA"6Dp;}Dv :�T(3# 5"&r�"9���+"07�*��(*��>@��+"3�$�{"�7�*�u�6vDE :"&%+���^�/�}Dp;�Y� Hh�RB�;0(9�!DE">P�

� :���K(8Dp@ :��#T'e�$�/�13"&�3DE�T�&@A�*�!�9@A�ZD�"K(*�!(91*1�@�`@A#�(�DE� "&�!"$rN :� ���"9?�8 |PA����*rE�LD:��E7�*��P{�*# "0th��q ���hD�;��P(jR� Z� :�w��13�w�(9# #T'!"�rGDp;{�

��Hh�RBCrE�T����T�$%$7�Dp;�����RB����5_ B&D�@�&'u;�(&5(3# R">PA�*���eD:�* v�!�T��(8DE�*�Aq+�E�~,I(*��(3�&(j�+D�;+�h�bvDE :"&%+���^_O���!"& �'mBjD�@�0'~1�@ : ����3DE#T'

@������ Et�(9'm�/}��?�(3#w@(8Dv�T��%uDE;���*rEr��81�D��T?����*�}"jr5(~�(3rE�� �r:"� v�h@A#T(8DE�T"&���@{R�T�$%a"j �(3#\(3�&�!�/�0� EDv :(8Dv��"0�a"jr��}�K%��8lβ

�E�*EDE �(3�&� "�#

��13"9�3D:�/�j@A"9@{R�N(S��!�AqL��d}�K%!�+"j R�RD�;�T�+�j �"&��h��1S'�13# "9�+;0(&R�T1*�:�A�T���T�`� :"&?+�T��%!�!�S�!"& :'��T�K�A"0vDE�!���"9�(S@{R(9#+th"&�!����t�;">�K(*'

P��(�D�(�;0�/%�;�� N :� ��KrE"& �y����E���z�"�EDv�!���"9�(*@{�(3#$th"&�!���Kth�LD�;K�!�S�!"j �'`� :"9P#2���e����w�`P"*DE;K(3 v�}���q

� � � ���� ��� Hh4.f ��� � ����� ��� ������ ����� � � �� ���� ��� � � �

f|;0�K��r:r��81�D�"&r\Hh4�f�"9�u1*"&%���LDE�T?+�hr�@+�1�DE� "0��T�&%~�T���"&��v�����!���jD��*���!���"9�(*@AR(3#�th"&�!����;0(&�P�*���~��?�(9#�@+(8D��*�e�/� �7W

HA

L author manuscript inserm

-00243083, version 1

� �

:�RDE :"���A��1�DE�T?��"& ~1* �"07��E���1�D�� "&��(3#!EDp@{�&� �*��C�8��� :"���A�*1�DE�T?��ED�@���2�6=(*��¬�8l�45,.f�q.<K"����RDE :�T�!���&DE(3#>�*rEr:�*1�D�;�(jCP+�*�*�

"9P{��� E?+�*�e�/�e(*�$'^"$rkD�;+�67�VvD�@��� �*5�7c{19���&Db�/�^"0��V��K(3# #�13 :"��7�ER�*1�DE� "&��(9#kED�@+�&'u�T��t�;�T1*;u�@ E%+��1*(9# #T'��!���"&�+(*@{R(9#Ath"0�!�*�

th�� x�uDv :��(8D��*�)t��LDE;�(*���6EDv :(3�&� "$#h�T�`�A#�(S�3D!(SP"9@jDa���O'��(& x^P��rE"j R�����jd ��q.�N�T%�;3D��*���-�+(3�T x^th�� x�=�V(�DE1*;+�*�)r:"& �(*%�3�������

�*�9@{1*(�DE�T"&�e# ��?+�*#/�A�"j19� "��E�*19"&��"&�!� 1hEDv(8D�@{7��(S�0�K"$1*1�@��(8Dv��"0�kq&�N4.fm@AR�8 R\;�(3�`�+"�"& :�� \�!���SDv(3#Ar:#2��cA�wP� # �LDv'e�� E@# �5 ���?�8 RR(3#T�N(S��

# "&�&%{�TD��8 ����7�� �"$���T1K�!���!"� v'}Dv;�(*�!D�;�K19"9�SDv :"�#�%� �"3@$�GiD�;�K�$��rEr��8 R����13�`t�(&�R�K(3#2#GP$@jD�R�w%���Tr���1*(S�3D���?���u(9r DE�8 �(31*1*"9@+�SDv�T��%

rE"& GD�;���/�01* R��(jR�5�T�����7� :�*�7� "&�K(*��!R"0�V(�D:�T1�R'$�K�jDE"&�eI�T�!�N4�f=@{R�� x.�2���C�AqL��d&��q*f|;�� :�5th�� R���"K���TrEr:�� R���13�*.�T�K(�D��3ED�"&r

�@{EDv(3�w��*�!(�D DE���3D���"0�~"& .�T�u(K1*(8DE��%"& v'e%+����8 �(8DE�2"&�VDE(&��Gq�f|;�`%� :��(8D\�K( �7"j ��LDE'u"�r."9P{7�8 v?�(8DE� "0�0(9#kEDp@{���2�6�(31�Dp@(3#T#T'~�@�%$%�6vDb(

�"�R�LD:�/?�m�*rEr:�*1�DK"$r`Hh4�f¡"9�-13"&%&��LD��T?�Cr�@��1�D�� "&���T��%�IP�@jDVP����*r:�LD:^�!�w%�;3DK%+# "9P(3#T#T'OPA�aR�K(3# #5(S��O :(8Dp;�8 >�T��13"&�7��EDE���3D:�

�T�`�{# �T1*(�DE�T��%)"&�#/' 7"&�!��x�{�*19��r��T1m13"&%&��LD��T?�Cr�@��1�DE� "0�$��E��*��P{�*#2"&t���qNf|;�~(SP{7���19�m"&rh(=�V(9 E��*�oPA����*r:�T13�T(9#Y�*rEr��*18D:>�T�

th"&�!����th�LDv;�(j�'��K�&DE"&�K(8D���1«�!���"&�+(*@{7�O13"&�K�(9 :�*�)D�"��'$�K�jDE"&�K(8D��T1)th"0�!��� �/��LD:�T(3#T#T'�# �*�-D�")Dv;�O;�'&�A"6Dv;�*R� CD�;�(8D

1*"&%���LDE�/?�-�/�h� �"&?�������SD�t�(&=�!"j ��-#T�T�+�*#T'�DE" P{�O(� :�3�@+# D�"�rC�T�h�+ x"9?�*� �9@(9# �LD�'�"jrC# �Tr:���9@{�mD�")DE;+�) :�*�"$#�@&DE� "&��"�r

�!���"&�(S@{R(9#Z�'$�h�jD�"&�!!�p?0(&R"&�!"*D�"j `�'��K�jD�"&�!`(*��m�����A :�*�R�/?�e�'��K�jDE"0�V(�D:"�#2"&%&'�:� 7D�;����"&�!�/�"m�*rEr:�*1�D �*�| :(�D�;��8 �D�;�(*�

rE :"&� (!�$�� R��1�D���rEr:�*1�D�"&r��*EDE �"&%����"0�^19"&%���LDE�/?�Kr�@��1�DE�2"&��T��%Gq+f|;0�� R�K� ���;"&th��?�� x���"0t 7"&�!�>��?�T�����13�K�/��x@����"& �DI"jr.(

�"��R�wPA# �����T :�*1�D��"���LDE�/?�h��r:r��81�D\"&r�Hh4�fO"&�!13"&%$��LDE�T?��r�@+�1�DE�2"&���T��%e��?+���^�w�!(&R'��`�jD�"&�K(8DE� 1��"�EDE�!���+"&�(*@AR(3#+th"0�!�*�!���j���

�jl�NR"5D�;�(8D��LD�� |�"��R�wP# �\D�;�(8D�P"*D�;!�&�T R�81�D�(S��`�T��&�T x��1�DN��rEr:�*1�D�|�V(9'K�T�3D:�� :(91�D�q

y��!"&�$%VDv;�h1*"0%���LD:�w?�`r�@+�01�D��T"&�5�">rE(3 .�7c(9�V�T�+�*�0��?�� EP+(3#G#2�8(9 E��T�$%e(*�+�!�!���!"$ E'�;�(*?�zP{�*���u�7cjD����$7�T?�*#/'^ED�@+��� �*�

@{R�w��%O���TrEr:�� x���3Dz :�*���(3 �1�; ���*��/%��*q�fN;��� R�6x@#LD:!�@$%�%�3ED�D�;�� x�^�V(S'mP{�u�/�K� :"&?+���!���jD��T�o?�� EP(9#\�{�� :rE"& ��V(S�13�*�|�"3Dv(*P#w'

?�� EP(9#\�!���!"j �'��;"&th��?�� x�\ED�@+�j�2�6`(9 :�K�+"6D�@$�0(S��T�!"&@AK�ER�*�!r�"j z :��?�� ��tV � d��$� � �&�EX�� �E��q ��� �@+(3#\�!���!"& �'~;�(jz�+"6D�P+�*�*�

�'ED����V(�DE�T1*(j#T#T'C��c��+# "& x�*����(*��`DE;�`r:��t�EDp@��� �*513"0�0�9@A1�D:�*�`D:"��&(8D��z;0(S?�`%�T?+���e13"0�SDv :(3�&� 1�Dv"j v'u :�*�@{#LD:5�;"&t��T��%C�*� Dp;�8 I�"

�*rEr:�*1�D ���j���mX&W�EX0U �:�mR"&�!���/�K� :"&?+���!���jD«th�LD�;��N4�f � ���$�mX�d��mX���«"j �����13#T�T�� t�;�� 1S;�13"9@{#T� P{�� :��?+�8 R��*�¬(3r DE��

�@����+# ���!���3DE(8DE�2"&�!th�LD�;���� ���"0%�6vD:�A�@�%�%+�6ED��w��%!(9�!(*�3DE(S%"&�� EDE�T1`�*rEr:�*1�D|"�r�� �"&%�*EDE�T�!� X�l���q&f|;0��PA����*r:�T19��(9#G��r:r��81�D\"&�>?� �@(3#

�!�*�!"& �'�G�Tr�(*��'��� �R�K(&#T#N13"&�`�(9 :�*�KD:"KDv;�z�{"��7�wP# �!��r:r��*1�D�"9�C?�� EP(9#��!���!"& :'u(S��u�K(*'m"9�#T'�PA�!��?� �$���019�*�u�T�~#2(3 E%���

R(*�`�# �3�@AR�T��%�()t`���$� �(*�&%�)"&r��+��@ �"9�{R'�1S;"�# "&%+��1*(9#YD��*ED:*qIy� :�*19���SD� ���?� ��t�"�r�1* �"07��E��*1�Dv� "&��(3#`(*���#2"&��%�LD�@�$�T��(3#

FG"�R�LDE �"&�V�|�!� �R� "0�Vf\"&�!"&%� :(S��;�'!��FG�Nf\�NED�@�&� �*."&r�Hh4�fa :��13�w��2���SD�\ x��?+�8(9# �*�h(�P{�RDEt`�*���K%0 �"9@��e���TrEr��8 R����13�5�T�`�(8D2DE�8 v�."&r

:��%�� "&��(9#�P �(3�T�K(31�Dv�T?�(8DE� "9����?"&��*�K�9@ ��T��%`�{�� :r�"j ��K(*��13�z"jr|���*#T(*'�*�}?�8 vP(3#+(*�+�hr��T%&@ :(9#+�!���!"j �'�DE(jx�$7��(&|th�*# #+(j\%� ��8(�D:��

:��#T(8DE�T?+�!PA#T"�"��mr�# "&t��T��1* R�8(&��*K"0?�8 5D�th"C'+�8(9 xK�w�~D�;+��;�w���"�1*(9�`��@{}(*���a"*D�;�� `�!�*��T(3#ND����`�{"& :(9#.# "9P{�uEDv E@1�D�@� ��3�D�;�(8D

�@�P{��8 v?���!���!"� �' � X � ��q

B��?+�8 �(3#A�;"& �DE1*"0�!�T��%.�T�K13"9%��+� D��T?��(j���6���!���3D�;�(*?+�.PA�*�*�K :��?� ��t`�*��P+'V4�� 13��(*��`_a"& R��*�&�+"6Dv(*P#w'Kth�LDv;V ���%0(9 :�5DE"

(8D Dv���3D���"0�~(*���13"&��13���3DE �(8DE�T"&���tz;�T1*;u;�(*?+�K�"*D\PA�*�����'$vD:���K(8D��T1*(3# #T'C��c(9�V�T�+�*�{q+f|;��'~(9#/7"uEDE R�*�����!Dv;�(8DNDE�*ED:z"&r�?� �@(3#

HA

L author manuscript inserm

-00243083, version 1

� �

�!�*�!"& �'�(j�x@��!�O�T�3DE(31�D^?� �@"�E��+(8DE�T(3#K�$�/�1* :�T�!�T��(�DE� "&��zP�@jD>D�;�� C�"&�T�3Du� = :(3 ��8#/'�1*"&��� �$�8 R�*�Aq5fN;���'� ��819"&�!�!���A�)D�;�

R�T�`@{#LDE(S��*"9@{O�7c(9�!�T��(8DE�2"3�¡"jrC?+�8 vP(3#>(*���?� �@(9#>�!���!"j �'�K19"9�13�7�jDCr:"& ��V(�DE� "&��(*��� R�8(&R"&���T��% � X�� ��q �h�*���wDE�aDv;{�

���TrEr:�T1�@A# Dv� �3��/��;�� x���3D5�T��D�;� �9@(*�3DE�LDE(�DE�T?�!�@+�K�!(8Dv� "&�m"jr�EDp@�&� �6zt`� Dv;Cth� ���*#T'C?�(3 ���(SP#T�eEDp@�&'m���67�T%�����(!�!�RDE(&��(*�(9#�'7�

;�(jz�"9���D�;+�*# �3�zP�*���C@�+���8 �DE(*�+���~P�'CHK"&%�� :?�"& xvD ���jX��qAf|;��! R�6x@#LD:zth�� x���& :(St5��rE R"&� DE;�}��T��>�!"& R�! �"3P$@{ED�ED�@+��� �*

"&?�� �D�;�>r:�T xvD��8du45,\f�1*(* E :�T�*�m"9@jD�P�*rE"& R�!W�$���3qAf|;�7' �@�%�%�*ED5�T�`� R"9?���e���3D�th�LD�;a�6vDE :(9�j�2"�#b"0�#T'a�2P�@jD�� �"3P+(*P#w'C�"*D

FG ����V(9 :�w��5t�;+�xDv;�� u"& !�+"6D�(&�R"&1*�T(8D��*�)t`� Dv;-(o� �"&%�*EDE(*%+���0��"&� D��6ED�C"jr��T�>�!�*���T(8D��m?�� EP+(3#z�!�*�!"& �'� ��*1*(3#T# �5?�� EP+(3#

:��(jR"0�0�/��%V(S��`�!"3DE"& bx�{�*�*�`(*��`(31*1�@+ :(31�'�0th�LDE;K�+"h19"&�R��EDE���3D|�8rEr��*1�D:."9�!"*DE;+�8 �?+�8 vP(3#+r�@��1�D�� "&���0?� �@(9#"& |?0� �@A"�R�+(8DE�T(3#

:��1*(3# # �Ith"& E�+�T��%)�!���!"& �'���$�T?� ���*�O(�D DE���3DE� "&����!���3DE(9#.DE :(91��0�/��%��"& >�!���3DE(3#�EDv(8D�@{Sq�fN;�*7�C?�8 v'-��{��13�Tr���1o�*rEr:�*1�D:eth�8 R�

�67����3D���(9# #w' "9P{7�� :?+�*� �w� R�*#T(8DE�/?�*#T'�'"9@+��% �@+ E%�T1*(3#2#T'��!���"9�(*@AR(3#Ot`"&�!����t�;" ;�(3�sPA�*��� %+�T?��� (s�!"0�SDv;�#T'

�T�3DE :(S�h@AR1�@#T(3 >�������*1�DE� "&��"jrm���O�K%-�*EDE �(3�&� "�#5r�"j ��O�!"0�SDv; ���jX��q|y� R�8�9@A1�DE� "&�����)�N4s�7c�� R�*�R� "&��"j >�w�-1�;"�# �/��8 v%�T1

r�@���1�D:�2"&�!(3r DE�� .�@{EDE(9�w��*�!�*EDE �"3%+���e# ��?�*#�;�(j\P+�*���! x�7�"& �D��*� �TWN�8�AX$X��t�;�� 1S;!13"9@# �>��c��A#T(3�T�>t5;�'e"&�+#T'e��(3 �#�'!(S���DE �(*�R� ���3D

�"�R�LD:�/?�m�8r�r:��1�D:�19"3@A#T�oP{�m��?�2�����13�*�Aq�<K��?�� �Dv;�*# �*���� ��6�@+# D��"&r�D�;�C�!��DE(&��(*��(3#T'R� ^th�� x��@+�0(SP# ��DE")��A�819��rv')t�;�RDv;�8

�9@ :(�DE�T"&���rE"& ��h@+#�(�DE� "&��$��"���*�$"j �� :"9%�*EDE�T�K13"9@#2�h(9# D��� N1*"&%���LDE�/?�.�A�8 �rE"& :�K(9��13�bDv"h(�1*#T�T�+��1*(9# #T'!R�T%��+��r��T1*(*�3D�# ��?�*#Eq

f|;0�` :�*�@A#LD:5"&rkDv;�K#T(3 v%��6EDI"&��%"��/��%e45,.f)"&r\;"& ��!"&��5D�;�� :(S��'�Af|;�Y��"&�!���{� .HK��(3#LDE;u�v�0�LD��T(8DE�T?+��_O���!"j �'mBjDp@�&'

�T��Hh�E_«B�.t`�8 R�`��@�PA# � �;�*����@{ED�(3r DE�� .D�;�}��@�P# �T1*(�DE� "&�m"&rZDp;�K�!��DE(&��(*��(3#/'$��/`"&rIHV"&%+�8 v?"& xED�¤@§�³ ¬ ��fN;�!vD�@�&'C;�(j�@{R�*�

"&�#w'u(`P :�T�*r\%#T"9P(9#��!�8(&�@ ��h"�r\13"0%���LDE�T?�`r�@+�01�D��T"&�~�TD�;�`�!"��$��r�� �*��_a_«B�N�\�T�!�A"�EDv�!���"9�(*@{�(3#At`"&�!���u(3%+�*�e��d>'+�8(9 x

"& �"�# ���� x�|rE :�*��"�r�� �"9P(*P#2�e�$���!���jD:�T(u(�D�P(3R�*#T�T�� �R�8�$���qG���uDv;��r:�T xED5(* v��"jr.Dv;� KED�@�0'$��t�;�T1S;mt�(&5D:�� ��!�T��(8DE�*�m��(3 �#T'

P�*1*(*@AR�5"jr�@+��(31*13�7�jDE(SP# �5�� �$�Y�*rEr��*1�D:.���T��1* R�8(&R�*�` :� R�!"&r�P+ :��(jED�1*(S�019�8 R�&;+�8(9 �D��&� ���(jR�*�+EDE :"9��5(S����$@#T�!"&��(3 v'!���KP{"$#�� 7�

�R�8��� �:�IUd��&Wot�"&�!���) :�*19�*�T?�*�O�&(3�T#T')"& :(9#Y�AqL�&Wd=�K%O"�r!,.�N���#w@{>WGqLd=�`% "&r`_aF�y �E19"9�SD��T�&@A"3@A!(9�&�!�T��� EDE �(8DE�T"&���K"&

�#T(319��P"AqAf|;�!�&_«B���!��(*�eD�"*DE(3#\R13"& :�*`�T�uP+"6Dv;C%0 �"9@��{`�T��1* R�8(&R�*�~R#2�T%�;3D:#w'm"&?�� .DE�T�!�e�p�!�*(9�~r:"&# # "0tz�2@$�a"jr�UGq Wu'+�8(9 xR�

�9@{��D�"u(�# ��(3 E�+�T��%m�*rEr:�*1�D�qA�\EDE :"9%�����{#w@{�� :"0%�6vDE�T�m��� ���"*D��T�K�+ :"&?�>%�# "9P(9#b19"&%&��LD:�T?+�Kr�@�1�Dv� "&�Ct�;���m13"&�`�(3 ��*�ut`� Dv;

�#T(319��P"u�p�!�8(9�u���Tr:r��8 ����13�*5�T�u�&_)B+� �1*"j R�*IP{�RDEt`�*���eHK4�f @$��8 R�(S���K�A#�(913�7P{">t�(j5�E�Aq�� �`@��+� D���+� ��AqL��d�d&��q&f|;��8 ��`t�(j

"&�#w'~(�R�K(3#T#N�T�+1* :��(j7�K�T�!D�;�`� �"3�A"& �DE�T"&�C"�r.th"0�!����R;+"&th�T��%u(>1*# �T��T1*(3#2#T'u�!��(3�+�T��%�r�@{#�19"&%���LDE�T?+�K���*13# �/��V�v"&r�WmB ���.�T�

D�;���*EDE :"0%���~�A#w@{z� �"3%+�3EDE�T�m%� :"9@�� �E��q l$���513"&�`�(3 ��*�eD�"�D�;�>�#T(319��PA"C%� :"9@�� ��UGq�j����q �h�� �'� ��*13���3DE#T'��D�;�u���13"0��~(9 E�

��W �j� �>;�'EDE�� R�81�D�"&�!� �9�*�ut`"&�!���� ��*13�*�T?��T�$%��&(3�2#T'~"& :(9#b�AqL�&Wd^�K%�"&r5,.�N��"& ��+#�(913�7P{"&��;�(jz(3# R"�PA�*���~(SP"�# � �;�*�C�9@{��D�"

��cA13�*�\"&rNEDE �"&���(S��`(*�K(*P{R����19�Y"&r�PA����*rE�LD�r:"& GD�;�I� :�/�V(9 E'K1*(3 :�&�T"&?�(j�1�@#T(3 N"9@jDE1*"0�!�3 �R�8�&W ��q �5@ ����$%V(5�!��(9�Vr�"�#T# "&th�2@+�

"&rZdAq U>'��(3 R��+�!��(*�u�&_)B+� �1*"j R�*�th�� :�h��q W+�K@$��LD:�# "&th�� �(S�!"&��%!t`"&�!���u(j�R�/%���*�hDv"e,.�|� 19"&�`�(3 ��*�!t`� Dv;!�+#�(913��P">�T�

(*��(3#w'7�6Vth�LDE;"9@jD519"&?�(3 ���(�DE�!(9� ��@{EDv�!���3D��2� k�AqL�&U$� �R�������q�[G"& 5th"&�!���a(&�R�T%$��*�eD�"m,.�N��19"&�K�(3 ��8�=t�� Dv;C�{#T(319��PA"��D�;�

:��#T(8DE�T?+�� :� ��e"&r\;�(*?�T�$%e(m�8���2@$�0�LD\���*1* ��8(&����/�^�&_«B�)R1*"& :�*5���mW~B ���|t�(&.�*EDE�T�K(8D��*�hDv"KPA�u�3q Ul��E,.�������3qL�&U��W�q �$l&�xq&f|;�

HA

L author manuscript inserm

-00243083, version 1

�}¸

(3�9?�� x7�h�*rEr��81�DI"jr\;+"j ��!"&�+��DE;+�8 �(*��'�t�(jI�!"& R�5� :"0�"9@��13�*�>(9�!"&��%�th"&�!���ut`� Dp;^#2"&th�� .13"&%����LD��T?��r�@+��1�D:� "0�e(8D|P(&��*# �T��

�2���k��q ������q*��;����!th"0�!���!t�;">����?�*# "9�A�*�K13"&%$��LDE�T?���/�h�(&�T ��!���3DN"& b�$���!���jD:�T(zth�� x�z��c19#w@{���*���&D�;+�5�!�8(9�!���Tr�r:�� x����19�5t�(j

�!"����� :(�DE�*�u(*�+���"C#�"0��%�� YEDE(�DE� EDE�T1*(3#2#T'�R�T%$��Tr:�T1*(*�3D�q+�E�CrE(31�D:�+D�;�`(31�Dp@(3#��K(9%���LD�@�$�!"&rbDv;�K���Tr:r��8 R�7�13�*z�T���&_«B�-R1*"& R�*

P�RDEth�*���uD�;��Dv x��(8Dv�*�u(*��^�{#T(319��P+"u%� :"9@��a� �DE"�"~��K(3# #GD�"�;0(S?�K R�*# ��?�(*��13�>�T�~19# �T��T1*(3#�� :(91�DE�T13�&qA� D�� z�T�K�A"j �DE(*�3D\DE"��"*D��6�

;"&th��?+�8 R�.D�;�(8D`D�;�a�&_«B�¡� u(oP� :�T��re��?�(9#�@+(8DE� "0��"&r>%�# "&P(9#�1*"&%���LDE�/?�mr�@�+1�DE� "&�����*R�T%���*����c19#�@AR�T?�*#T'OD:"-�1* :�*���-r�"j

�����!���jD��T(a�T�-�*#2���8 �#T'-�@�P �7�*1�D:�i��LDK1*(9�&�"*D`PA�m13"&�R� �$�8 R�*�)(&�(a1*"9%����LD:�/?�uP+(8D DE�� E'�5�LDK� ��T��(*���+ :"9� :�T(�DE�~r�"& K@{R�m�/� D�;��

�"9��@#T(8Dv� "&�Kth�LDv;V(5t`� ����(9%�� :(S�j%+�6�+� .�/�0(9��� �9@(8Dv�Yr�"& N���RD:�*1�DE�/��%V1S;�(3�&%�5(91* :"���DE�T�!�*�+(*�+�K�/.x@�P ���*1�DADE"`13�*�2# �T��%!�*rEr��*1�D:\�T�

�"&��E�$���!���jD:�/�j%m�@�P ���*1�D�*q+� D�� 5(9#/7"u�T�$?0(9# � �KD�"e19"&���2���8 5(S�^�LD������ �&@A�w?�(j#2���SD|D:"�(ex�{��13�Tr:�T1>13"&%��+� Dv�T?��D��6ED7qf|;�K����Dv(3�T# �*�

�*rEr:�*1�D�"&�K�T��&�T?+� �9@(3#+13"9%���LD��w?�bDE(&��\� .�7c��{��1�D��*�YDE"zPA�.��@�P+#�� �;�*�K#T(8DE�� 8q

Hh4�f ��� � � �� �

������������� ������������������������������� ����"! #%$&��#���'�#���()��*&#����+��'���,���-#.0/�$&�,��#

B�wcjDv�*���~"9P{��� E?�(�DE� "&��(3#�ED�@�$� �6�;�(*?�zPA�*���!��@�PA# � �;�*�>PA�xDvth�*���)�8X �9Ue(S���W���&WKDE"���?0(9#w@(8DE�5D�;�z� ���?���3D:�T?+�K�8rEr��*1�D

"&r�Hh4�fs"&�-Dv;�O :� ���"�rC����?�*#2"3�A�w��%��+"0vD:���!���"0�(*@{�(3#K�����!���jD��T(q`B+��?����1*(j7�6��19"&�3DE :"$#!ED�@A�j�2�6O�&� � �"*DC�T��&� 13(�DE�O(

R�w%���Tr:�T1*(9�3D���rEr:�*1�D�g&DEt�"~�TDv;�K"�#2���6vD�ED�@�$� �6���R;"0th�*�u(K�+"&��E��T%&��Tr�� 1*(*�3D.�T�+1* :��(j7�*�e �� R�~"&r������!���jD���(>(*�!"&�$%eH`4�f«@{R�� x

1*"&�K�(9 :�*�5DE"��+"&��2@{��� x �R���&U�|�8��d�:�*Dp;0 ��*�Y�;+"&th�*�`�"`���Tr:r��8 R����13� �R�8�������8� � ��(*��5DEt�"`r:"9@+��h(��0"0�{�ER�T%��+��r��T1*(*�3D����*1* R�*(jR���

:� ���"&re�$���e���3D:�T(O(9�V"0��%)@{7�8 Ru19"&�K�(9 :�*�aDE"���"&�&@{7�� x �R�8��X$�����8���q ��� D�;�O"*Dv;�8 >;�(9���0����T�+�aED�@A�j�2�3C���+���T1*(8D��*�)(

R�w%���Tr:�T1*(9�3D|� :"*D��81�D��w?�K�8r�r:��1�D."&r\Hh4�f5g�rE�/?�h1*(&R�3��13"0�SDv :"&#NED�@�&� �* �R�����������8d�.R;�"&t`�T��%e(KU ��Dv"e��l��¬ R�*�9@1�D�� "&�e�/�e :����u"�r

����?�*# "9�A�T��%Ky��h�$(�1* :"��7�E���1�D:�T"&��(9#GED�@�&' �R���8� ���;"&t`�T��%el����¡"&r� :� ��V R�*�9@1�D�� "9�!(*��5Dv;��19"&;"& �DNEDp@�&� �3��$�T����T1*(8Dv�T�&%!(�UN�

DE"m��X�� R�*�9@1�DE� "&�a�/�^Dv;�� :� ��O"jrz����?�*# "9�A�T��%my�� � ����������l����$� � ��q�4��7%0(9 :�&�T��%C�A"07��wP# ����"�����*rEr:�*1�D���N"0�#w' "&��uEDp@�&'

:�7�"& �D��*�h(���*13�*�R(9 E'K�K�T��T�K@+���j(9� #T'!��"�7�5"jr5�3q WdV�K%},I�N���R�8��X �:�&t�;+�8 R��(j���(9 :�w�&%�¤@§+³ ¬ �rE"9@+��`�"K�@1*;!��r:r��81�D �7����W ��q

� DN� \@$�019# ��(3 \��r|(h1� :�LDE�T1*(3#A�9@ �(8DE�T"&��"&r�Hh4�fO� \����13�3��(3 E'hD�"`;�(9?�5(��+ :"*DE��1�DE�T?���*rEr��*1�D�q����TrEr:�� R���3DbED�@+�j�2�6��T��&� 1*(�DE���"R�LDE�/?{�

�*rEr:�*1�D:z(3r Dv�8 ����K"&�3DE;���"0��6��DE;� :�*�*�N7��?����N"& .DE���C'��(3 x � ���8�5���$�8�5���RW�5�$� � �Rqf|;�� zth� ���K �(*�&%�!"9P{7�� :?+�*�ur:"& 5"9�jD:�/�V(&#

DE :��(8Dp�!���SD|�9@ :(�DE�T"&�!� |� :"9P(SP#T'K�K(j�/�0#/'! :�*#T(8DE�*�5D�"YDv;�bD��T���T��%!"&rADE;�\DE R�8(�D��!���3D�q �b(*��$�R¤@§+³ ¬ � ����A"& �DE�*�K ��*13���3DE#T'�DE;�(�D�� :�T"&

Hh4�fC@AR�.t�(j\(&�R"&1*�T(8D��*�`t�� Dv;K x���9@{19�*�h �� R�K"�r�y����TD�;�5:Dv :�7��%3DE;!"&rAD�;��(j�R"$1*��(�DE� "&�!�/�01* ��8(&R�T��%Kt`� Dv;�D�;�5�9@ :(�DE�T"&�!"&r{Dv;�

�(jvDD� :��(8Dp�!���SD��:�0P�@jD�t��LDv;"9@jD�(*�&'K(*���+(* :���3D�P����*rE�LD�t��LDv;V1S@ E :���3D�Hh4�fC@{R�.@$�0#2�6�.x@1*;`@{R�5�7c13�*�*���*�C�8�V'�8(9 x � ��� �xq

���hDv;���(jED|rE�w?�5'��(3 R��+rE"9@ N�!�RDE(&��(*��(3#T'7�6Z;�(3?+��PA�*���K�A�* :rE"& E�!�*�>rE :"&��Dv;�5(*P"&?+��vD�@��� �*��+19"&��13#w@{�&�T�$%hDE;�(8D�D�;��8 7�

� �(KWX�� �R����X�:�G�&U+� ��� � �:�G� �&� � X$��b(S���!U�U� �R��W+��:�A ��*�3@A1�DE� "0�^�w�KDE;�z :� R�u"&r.����?�*#2"3�A�T��%u�����!���&D:�T(K�w�VDv;�z%0 R"&@$�^"&r

��?�� N@{7�� x."&r\�6vDE :"&%+���$�+19"&�`�(3 ��*��D:"`���?+�8 |@{7�8 R*q&���!(3#T#G1*(&R�*��&D�;�5(*@&D�;"& xI���K��;�(jR� �9�.DE;��� ��67���19��"&r��{"�����PA# ��PA��(&R�3

HA

L author manuscript inserm

-00243083, version 1

¿)À

(*���u#T(31��C"�r.13"&�3DE �"&#Nr:"& .�+"6D����3DE�T(3#N1*"0�r:"9@���$�8 R��@1S;^(&5�*�9@{1*(�DE�T"&�������� :�*�7�T?�KR'$�h�jD�"&�K(8D�"&# "&%�'u(*�+��y5�{"&�«%���"*DE'&�A�6�

�T��(3��� �9@(�DE�)�T��r�"j ��K(8DE�T"&�� ���%�(3 :�&�T�$%-D�;�)�*rEr��*1�D:m"&r>� :"0%�6vD:�w��@{7�6��Dv;�O�3EDE :"9%�����+ x�7�(9 E(8DE�T"&���z��"���«"j ��3@+ :(8Dv��"0��"�r

D�;�� :(S��'Gq&fN;��`�8rEr��*1�D:�"jr�DE;�*7�5�{"�����PA# �5�!��Dv;"��&"�#2"&%�T1*(3#�# �T�!�LDE(8Dv� "9�$Yth�8 R�5�+"6Dv(*P#w'!;+�T%�;#T�T%�;3D��*�`P'KD�;�`�&� rEr:�� R���019���T� �z4

"9P{��� E?+�*�!tz;���!13"&�K�+(3 :�w��%hDv;�5 R�6x@#LD:�"jr�DE;��EDp@{���2�6I1*(3 : ��T�*�!"9@jD�PA�*r:"& ��e��X�X&U�;¨ �l¤��A# �*�I :"9P�@{ED��$t��LDv;e# �*���@�P ���81�D�8�+(S�0�

th�LD�;�#2�3�m ��T%�"j R"9@{oEDE(8Dv�/vDE�T1*(3#K(*��(9#T'�� a� ��4 �3qL� �)�+"6DCR�T%��+��r��T1*(3�3D�(*����;�"&th�T��%�;�T%�;�;�RD:�� R"3%+����*�LDE'��th�LD�;�D�;�(8D

��� :r:"& ��!�*�`(3r DE�� ��8X�X0U!� �54 ^��q U+Xj�$R�w%���Tr:�T1*(*�3D�(S���?+�8 �'K# "&t�;�xD��� x"0%����*�LDE'�� �R��W� ��q

������������� ������������������������������� ����"! #%$&��#���'�#���(������#�� ����� ��� ������ ��#%��� ,��������� ������

f|;0�� R�819���SD| :�*�@A# D�\"�rAD�;�.��HK�E_)BKt�;+��1S;Kt�(j\1*(3 � :�T�*�K"9@0D��/�V19"&�K�K@�+� Dp'{�E�&t`�*# #T�T��%Kth"&�!���!(9%�*�K��d5D�"Vl$X`'��(3 R��

(3 ��.��"*D�13"&�7�/vD:�7�3D�th�LD�;�DE;+��r:�/��&�T��%."&r��!�*1S;0(S�� EDE�T15(*��K"9P{7�� E?�(8DE�2"&�}vD�@��� �**q9fN;��\��HV�E_«B!���*R�T%��!�/�j?+"�#T?�*�`(�UGq Wz'�8(9

�&(3� #T'K"& :(9#(9�&�!�T�� EDE �(8DE�T"9�!"&rN,.�N�a�E�AqL�&W+dz�K%0���#w@{\_oFAy���WGqLdz�K%��:�0t�;�T1*;Kt�(j\"9P{7�� E?�*�5D:"`# ��(&�YDE"`(�D�t`"0��r�"�# �`�T�19 :��(jR�

"&rND�;�K :� ��ur�"j I� :"9P(SP#T�K�����!���jD��T(e��(3#T#����������SD��T(hD�'&�A�6����T�uWX&U+l>�"�EDv�!���"9�(*@{�(3#�th"&�!���~��H`4�WGqL��d&��,.�����h�9q W|�8����q U �3��q

<K"~7�T%���� rE� 1*(S�3D5���TrEr:�� x����19�e�/�~y��  :� ��mt�(&�rE"9@+��~r�"& ��8�wD�;�� ZDp;�hDE ��8(�DE�!���3D5"& ��#T(319��PA"~(9 E�!`"&rbDv;�eEDp@�&'��R��WN� ��qAf|;�

R�w%���Tr:�T1*(9�3D.�*rEr:�*1�DI�T�!D�;� �ED�@+�3'�t�(&5 :��#T(8D��8����cA1*#w@{��/?�*#T'!DE">?�(jR1�@#T(9 ������!���3D���(&��t�;�� 1*;�t�(j5�/�01* R��(jR�*���T�!Dv;�5DE :��(8D��!���&D

(3 v� ���7WGqLd��u�|� kd�¥v± �.UGq�j���|� ��!�/�~D�;�>�{#T(913�7P{"=%0 �"9@��{��q�f|;����&@�`PA�8 K"&rzth"&�!���Oth�LD�;a(�;� ED:"& v' "&r�1*(3 ��&� "&?�(jR1�@+#�(9

��� ���(j��`t�(&I;�T%�;�� .�T�!D�;�5DE ��8(�DE�!���3D�DE;�(S�^�/�VDv;���+#�(913�7P{">(3 v�}��(KrE(31�DE"& .tz;�T1*;u� 5# �T��*#/'VD�"!;�(S?�V��T%���Tr:�T1*(S�SD�#T'�(3r:r��81�D��*�

D�;�C"9@jDE13"0�!�a�E��*�C(3# 7"aPA��# "&th��q\���)Ud��&W ;j'ED��� x��1�D�"&�!� �3�*�oth"0�!���$��(OdAq WO'��8(9 !�&(3�T#T')(3�0�!�T�� EDE �(�DE�T"&�)"�r!,.�N��(9#�"0�{�

�E�AqL�&Wd>�K%������ �>�"*D�7�T%&��Tr:� 1*(S�SDv#T'u�!"����2r�'}Dv;�` :� ��^r�"& .� �"3P+(*P# �K�$���!���jD:�T(���(3#T#ADE'&�A�6R�.19"&�K�(9 :�*�KDE"KDE;+���A#T(313�7PA"!%+ :"9@��

�2Hh4��9q U+Xj��,.� ��� ��q �&����WGqL���&� �R��W$W ��q����!D�;�� .DE ���(9# �Dp;���+ :"9�"& �DE�2"3�C"jrIth"&�!���ut`� Dv;�?�(jR1�@#T(9 x��y���"& .�!�wc{�*�������!���jDE� (}t�(j

# "&th�� �D�;�(S�a�T�^Dp;�>�#T(313�7PA"C%0 �"9@��kq�FG"�"&# �T�$%a�j(�DE(urE"& 5P"*D�;uDE ���(9# K�E,.�N��(9#�"0��!(9��m,.�N���«_aFAy��:��D�;��"9?�� :(3#2#NHK4�rE"&

� :"9P(SP#T�5�����e���3D���(�t�(&`�3qLl��K�E,.� ��� �9q���X���WGqL���&��qSHh4.fa��rEr:�*1�D�\"&�K�!� # �`13"&%$��LDE�T?�5�T�K�(9�T :�!���3D|�j�2�`�"*DNR�T%���Tr���1*(S�3D:#T'!�$��rEr��8

P�RDEth�*����%0 �"9@��{�tY;+��D�;�� bD�;�`t`"&�!���uth�� R�YDE ��8(�D:�*�>th�LDv;�,.�|� �o_mFAy��2Hh4¬�3q ��l$�G,.� ��� �AqLl&U���3qLd�d&�\"& .t��LD�;~,.�N�«(3#T"&��

�2Hh4��3qL�&U���,I� � � �AqLX�d����3q�jX0�G"& �(3r DE�� ��"&"�# �w��%�D�;�5�&(8Dv(h�2Hh4��3q Wd&��,.� ��� ��q X$l����3qL���&� �R��WN�8���7W�W ��q

f|;0�>?�(3#2� �&� Dv'a"&r513"&�`P{�/��T��%uD�;�`DEth"C(*��(9#T'��*��\,.�N��(9#�"9��>th�LD�;a,.�|���G_oFAy���(jzt�(jK��+�819��r�� �*�m�T�uD�;��"& :�T%+����(&#

� :"*DE"&19"�#T�b19"3@A# �}P{���9@{�*ED�� "9��*���A(jIPA�6�� ���*�;�(3?��T�$%!@+����� E%"&�+�h�@ v%�T1*(3#��!���"&�(S@{R�*��th"&�!���~�w�!D�;�K,.�N�O(9 E��(9#/�"!;�(&�

# "&th�� z�!�8(S�a�*�3@A1*(8Dv��"0��(S��~rE(9�!� #/'��T��19"&�!�3��|# "&th�� 5P(&R�*# �T����&_)B+��R1*"& :�*��|th�*�T%&;�*�=�!"& x�*�|1*"&��@�!�*�m#2�6�`(9#T13"&;"&# �

(*���>;�(3�>�!"& x�z1*(3 :�&� "0?0(&R1�@#T(3 .�&� 7�8(&R�6�{;�'&�{�� �D����R� "&������T(*P�RD:�*���(*���>?0(&R"&�!"*D�"j �x'��h�&D:"&�!*q0yh#LDE;"9@+%�;VDp;���&@+�hPA�� ��(* ��

��K(j#T# �AD�;+�!�T��13�2�����13�>"&rY�$���!���jD:�T(�(*���u_O,.���/`����� ;��T%$;�8 5�T�C;�'ED��8 ��*1�DE"&�!� �9�*�ut`"&�!���^Dp;0(9�~�/�eDE;+"07�Kt`� Dp;~(>@jDE�� E@{��

:��%�(3 ��&# �67K"&r.DE R�8(�D��!���3D�t`� Dp;mHh4�f�"j ��#T(31*�7P{"Aq�� D�R;"9@A# �C(3# �"�PA�!�!���&D:� "0��*�eDv;�(8D5(SP"9@jD5Ud�� "�r.Dv;�>th"&�!���O�T�^Dv;�

HA

L author manuscript inserm

-00243083, version 1

¿ �

,.�N�\��(3#T"&�����HV�E_«B!DE :�T(3#�;�(3�K�+ x��?�� "9@{7#T'KDE(*����>Hh4�f ¥v± �k�������w�KDE;�`,.�N����_aF�y�%� �"3@$�kq�F� :�T"& \@{��`"&rNH`4�f)(S�����8(9 :�*�

DE"!R# �/%�;3DE#T'e ��*�9@13��Dv;�5 :� ��!r:"& |� :"9P(SP# �����������3D:�T(`(3#LD�;"9@+%�;!�"*D\R�T%���Tr���1*(9�3DE#T'e�pHh4��Aq�jl��A,.� ��� �AqL�&W��WGqL��X0�:�+1*"&�h�+(3 :�*�`DE"

�3qLX�d��E,I� � � �AqLX&U��UGqL�&U$�mrE"j o���?+�8 =@{��� xSq�y`#�#>D�;�*���19"&�R� ���� :(�DE� "&�)�;+"3@A# ��;�(S?��P{�*����DE(*����¡�T�3DE"�(31*19"9@��3Dmt�;+�*�

1*"&�K�(9 :�w��% "& `�"$"�# �w��%�Dv;�!Dpth"~��HK�E_)B)�w�3D��8 v?���3D:� "0�$SqN[A@� �D�;��8 K(S�0(9#w'$7�*��6vD:�T�K(8Dv�T��%)�8(91�;Oth"&�K(3�o�"�EDv�!���"&�A(*@{�(3#

��c$�{"��@ ��.DE"K�����"&%+���"9@{\(9�0�>��cA"&%���+"3@A.�*EDE :"0%�������/��D��* E�!."&r�'��(3 R.R�w�13���!���"0�(*@{��Y"& |;�'EDE�� R�81�D�"&�K'!(3 ��� �� �3@A�T :�*���

;"&th��?+�8 R�3D�;+�.�&@�KPA�� N"&rGt`"&�!���!�T�!��(31*;K1*(8Dv��%"& E'K�K(*'`P{�\DE"�"KR�K(3# #&DE"K"9PjDE(9�w�V ��*# �T(*P# �5�*EDE�T�K(8D��**q

���m13"&�1*#w@{7� "&���D�;����� R1* ����(9��13�2�6zPA�xDvth�*���uDE;+�h� Hh�E_)Ba(S���m"6Dv;�� hED�@+�j�2�6V�V(9'CP{�>(8D DE ��wP�@jDE�*��D:"C(��&@+�hPA�8 `"&r

rE(31�DE"& R*q5[G�T :EDE#w'�zth�LDv;� :��%�(3 ��)DE")DE;+�a�+(8DE� ���3D�%� :"9@��kgz�T��Dp;�m��Hh�E_)BA�zth"&�!����th�� R�)"�# ���� �D�;�(*����d��`rE(9 ~r� :"9� Dp;{�

��� :�T�!���"0�(*@{����A�8 �� "��>(*��`DE;&@{�?+�8 v'^�$��r�r:�� R���3D.rE �"&� Dp;�`@{�@(9#G1*# �/��T1*(3#k7�LD�@(�DE�T"&�u�T��t�;�T1*;>Hh4�f)� I� ��671* :�wPA�*�!(3 �"9@��

�!���"&�(S@{R�&q3f|;��'Kth�� R��(9#/�"K# �67\;��(3#LDv;�'�&th�LDv;V1*(9 :�&� "&?�(&R1�@#T(3 N �� ��V(�DG �(*���&"&�!� �*(�DE� "&��0th�LDE;K(*�!�7c13�*�I"jr�;�'&�{�� �D����R� "&��

"9P{�*��LD�'�|(*���DE"9P(91*13"�@{����R�8��� ��q�f|;�K;�/%�;a�& :"9�{"9@jD5 �(8DE�>�w�~��Hh����U�W� ���uDv;�KHh4�f�%� :"9@��a(S��m� �j� �T�uD�;�>�#T(319��PA"

%� :"9@���:�ADv;�}�!"j R�>rE x���9@{���3D�@��&PA# �T��&�T�$%��T��DE;�}Hh4�f�%� �"&@��uD�;�(*�m�T�eDv;�K�#T(913�7P{"�%� :"9@��{�ADv;��Dv'&�{�>"�r�r�"j ��`@{#T(�DE�T"&�=��"& �(3#

,.�N�«(*����_aFAyh��tz;0�21*;u� �� :"9P(SP#T'!Dv;�h19"&�KPA�T��(8DE�T"&�~"&r�(Kth��(*�u�+��@ �"9� :"*D��*1�DE�T?�>�6EDv :"&%����th�LD�;u(3�u�T�+�*rEr:�*1�DE�T?+�6���TrI�"*D

(*�3DE(S%0"0�� EDE�T13�\� �"&%�*ED��T���R�*��P{�*#2"&t��h(&>th�*#T#5(j`D�;�C��"R�*}@{7�*� �pt�;�� 1*;O1*(*�oP{�C13"&�R�2���8 R�*�o(j>;��T%�;)rE"& K(mrE�T xED���#��/�{�

DE :��(8Dp�!���SD��/�!"j#2���8 ��"�EDE�!���+"3�+(*@{R(9#�t`"&�!�����(3 ���(3# R"`1*(*@AR�6\"$rk1*"0�13�� E� �R��W���q

f|;0�5�T��1* R��(jR�5�T��DE;+�� :� ��V"$rN����?�*# "9��/��%!�����!���jD��T(��T��D�;�h,I�N� �u_aF�y-%� �"3@$�e�2P�@jD��"*DN�w��DE;+�Y,.�|�m%� :"9@�����V(9'`P{�

�9@{���+ :�T�K(3 �� #T'�Dv"a(*�)�T��1* R��(jR�C�T�O?�(jR1�@#T(9 K :� ��GqNf|;��/>� >(3# R"o13"&�R� ED����3D`th�LD�;�Dv;�~���8� �T��1* R�8(&R�C�T� � 71�;���!� 1m:DE �"9�{�

(3#T :��(3�0'! x�7�A"j �DE�*�!�/�hDE;����Hh�bEDp@{�&'!(9r D:�� .dAqL�`'��(3 R."&rb,��N� �C_aF�y-DE :��(8Dv�!���3D �R��W�U �E�N(9���hDp;��;+�T%�;!(*�+�K :(*�+� �!�T��19 :��(jR�

�T� �$�*��� ?+���"9@{�Dv;� :"&�KPA"�R� ��\t�;+��1S; �T��1* R��(jR�*�=P' �AqL����r�"�# �m(9r D:�� h"0�#T' "0��u'+�8(9 h"&r5DE :��(8Dv�!���3D��R��Wd ��q\B{�T# ���3D`13�� R��P+ :(3#

�T��rE(3 �1�D:�(*���O�!�T1* �"��?�(j�1�@#T(3 !1�;�(S��%�*u�w�-���*����t�;�LD��C�V(�D D��8 >(3 :���"&t� ��*13"&%&��T�3�*�oDE"oP{�m�T�K�A"& �DE(S�3DK :� ��)rE(31�Dv"j R�rE"&

?�(jR1�@#T(9 �(*���C(3# �"Cy���D�'&�A�u�����!���jDv��(& �R��W���q�f|;0�>?�(j�1*@#T(3 5 ��/x�m;�'&�{"*D�;�*7�/}� `(3# R"m�@����A"& �DE�*��P'a"9P{7�� E?�(8DE�2"&�5D�;�(8D

(3�9?�� x7���*rEr:�*1�D���@1�;�(jZ?���"9@{NDp;0 R"&�`PA"07� ��+1*"& R"3��(9 E'!;+�8(9 �DN�&� 7�8(&���"& .EDE �"3�+�6��"j191�@ |?�8 �'��8(9 :#w'e�T�hDv x��(8Dp�!���SD��A"&r�DE�����T�

D�;��rE�� RED�'��(3 ��R�7Wd��q

yh#LDE"&%+�xDv;�� x�AD�;+�h��Hh�E_«Bm :�*�@#LD:`��"��+"6DI� �"&?��Dv;0(�D.H`4�f�;�(j���"~��r:r��81�D5"&�Cy��h��P�@&DbD�;+��'~13# ��(3 �#w'��T�+���T1*(8DE��Dv;�(8D

th"&�!����"�# ���� GD�;�(9�}�$d`'��(3 R.�;"9@{#2�`�"*D�P{�\DE R�8(�DE�*�Kt��LDE;e,I�N�Cth�LD�;�"j �th�LDE;"9@jD�_oFAy)D:"`(8D2D:���`�jDAD�"�� R��?���3D|�����!�*�3DE�T(`"j

����;�(*�19�K13"&%$��LDE� "&�GqAf|;��h��Hh�E_«Bm���67�T%���t�(&5@$�$x@{�LDE(SP#T�Kr:"& .D�;�!�/��?�*EDE�T%�(8Dv� "&�m"jr�(>���@+ :"9� :"*D��*1�DE�T?�>�*rEr:�*1�D:��(*���~�LD��

;�(3 :�&#T'a�@ v� :� R�w��%uDv;0(�D��"�� :"*D��81�D��T?���*rEr:��1�D5t�(&`r:"9@���Aq�[A@+ D�;�� :�K"& R�6��D�;�> x�*�@#LD:}"&rZDv;�`��HV�E_«Ba1*"9@{#2�~(9#/�"C�"*D�P{�

��c&DE :(S�"&#�(�D:���hD�"!"*Dv;�� .1*"3@+�3DE :�2�6����6x�{�*19��(9#T#T'e��@+ :"9�{�zt�;�* ���"*DE;+�8 \Hh4�fo@{R�w��%!��(�D�@ :(9#kEDv�8 �"j�2�K;"& ��!"&��*5�<¤��  �G�*EDE :(9�& :�T"�#

HA

L author manuscript inserm

-00243083, version 1

¿)¿

(*���>� :"0%�6vD:�� :"&�+�*�.(*��u"*D�;+�8 ��!"����*z"jr.(9�&�!�T�� EDv :(8Dv��"0���2DE E(*�R�$�8 ��K(3#s¥v± ��"& :(3#��!"����*�.(3 ����+ :��r:�� : :�*�Aq+f|;�67�`���Tr:r:�� :���+13�*

�T�K1*# �T��T1*(3#$� �(31�DE�T1*���V(9'`P�� R��#T(8D��*�YDE"`# �*�|;�(3 ��Kr�@#A�8r�r:��1�Dx.�E��*�.PA�*#�"0th��(*����@+ E%���3D�#T'K�!�8 ��LD�r�@ �D�;+�8 N�w��?+�6ED��w%�(8DE� "0��q

�"������������ ��� �-���-,����#����������� �-��� ������������ ����"! #%$&��#���'�#��

f|;0�z�8rEr��*1�D:."&r�Hh4�fa"9�!t`"&�!���!th�LD�;>y���;�(*?��PA�*���e��?�(&#w@(8DE�*�K�/�!�*�T%�;3DADE;+�8 �(*��7@jDE� 1.DE ��T(3# .�E�T��19#�@A���T�&%!r��T?��45,.f\��q

fN;���'�;�(*?�«PA�*����@+�0(SP# �aD�"������!"&�{vDE :(�DE�)(�1*# ��(3 CP�7��*rE� 1*�T(9#e�*rEr��*1�Dm"&rm�6vDE :"&%+����Dv;�8 �(*��'�"9��y�� ���?+�8 �� Dv'Gq�_o"j R�

�(3 Dv��1�@+#�(9 :#w'�&D�;��Dp;0 R�*�5�!"+EDN ��819���SD|13"&�3DE �"�# # �*���+��"9@�PA# �*�2P{#2�T���D�;�� :(S��7@jD:�T1�Dv :�T(3# ��+1*"&�+�3@+1�D:�*�`P+'KHV���+���8 R�"0��¤@§;³ ¬ � �����Wl�:�

_m@#w��(3 ��ʤ@§�³ ¬ �R��W � �h(9���m��(*��% �R��WX�K"9P{7�� :?+�*�a�+�*� Dv;�� K(aEDE(�DE� EDE�T1*(3#T#T')��T%&��Tr�� 1*(*�3DzP{���+�8r�� D}"jrK,.�|��r�"& K(*��')"&rYDv;�

�T��&�T?�2�3@+(3#A13"0%���LDE�T?�`"& br�@$�1�DE� "&��(9#A(j�7�67R�!���3D:��$�+"j \(`���*1* :��(j7���T�hDv;�����?+�8 R�LD�'e"$rb�����!���&DE�T(h(9r D:�� b(z'��(3 \"&rGDE R�8(�D��!���jD�q

���e(!��V(9# # �� .4Y,\fOt��LDv;eW�}�"�EDv�!���"&�(S@{R(9#Ath"&�!����t��LDv;�y �`�AyhEDp;0(S��(�¤@§$³ ¬ �G ����"& �DE�*���T�K� :"0?���!���jD\�T�e(�D DE���3D�� "&�e(S��

R"&�!�}?�8 vP(3# ��?�� �@(3#�(9���u����!(9�3DE�T1K�!�S�!"j �'!DE(&����w�Cth"&�!���u@{��T��%u(e��+�T���(8DE1�;C"�rK�8lβ

���6EDv :(3�&� "$#��E��q��z�K%���&(9'0��rE"& �

th�*���{���1*"&�K�(9 :���hD�"!t`"&�!���e R��13�*�T?�/��%!�#T(913�7P{"��R�8�����q+f|;0� 5��rEr:�*1�D|t�(j��T�+�����A��������3D."&r�DE;+��;"& ��!"&��`��r:r:��1�D."&�>�!"�"��Aq

y�r D:�� Z7��?�� :(9#Ath�*���{�"&r�DE :��(8Dv�!���3DNt`� Dv;�& :(St�(3# �&D�;���/�K� :"&?+���!���jD|t�(&I�"!# "0��%�� .��?� �����3D�q&�v�!(h ��*13���3D|�!��DE(j��(S�0(9#T'{R� �"&r

rE�T?�C4Y,IfZ>�w��13#w@{�$�T��%)WN�8�ot`"&�!���)th�LDv; y��h�IHK"9%�8 �?"$ xEDQ¤@§�³ ¬ �51*"9@# �O"&�#/' �$���!"&�{EDE �(8DE�C( x;0"& �D�DE�� E����W)�!"&�3Dv;R�

�"�R�LD:�/?��DE R��(8D��!���3D��8rEr��*1�D."&rkDE �(*�R���� ��V(&#��*EDE :(9�&� "�#k�2P$@jD\�"*D."&r.,.�N�N�."0�e?+�8 vP(3#��!���!"� �'^�v"&�e1�@A�*�u���*#T(S'�*�! R��1*(3# #�"&rb(

th"& :�C#T�/vDE�.P�@&D.�"*D�"&�u?� �@+(3#|�!���!"j �'��#T(*�$%j@+(3%+�Kr�@��1�DE� "0�$7���!"�EDYx�{�*�*���*�>D:�*ED:���1*#��/��T1*(3#N �(8DE�w��%��1*(3# �*�"& 5���7� R�6�R�T"&�Gq

fN;���'a(9#/7"m :�7�A"j �DE�*�m(�?�8 �'a# �/�!� D��*�C�A"0�� D��T?���8r�r:��1�D�rE :"0� # "&ts��"�R(*%��"jr`,.�N���E�AqL�&WdC�K%�E�&(*'��5P�@jD��"*D�rE �"&� ;+�T%&;�8

��"�R(*%+�!���3q Wd��K%��Y"0�eD�;�}%# "9P(3#|_a_)B+���1*"j ��K"&�#T'C(3r DE�� 5WC�!"3�3Dv;5P�@&D.�"*D�(3r DE�� ����N��(S���)��WC�!"9�3DE;`"&rbDE ��8(�D��!���jD�q

��;�RDE;+�8 5(*%+�6�|�����!���jDE�T(u"9�7�xD5"& .D�;�`@{7�!"$r�(>�(* �Dv��1�@+#�(9 ��0 ����+(3 :(�Dv��"0�~r:"& 5(�#�"0��%�� Y�9@ �(8DE�T"&�m"&rbDE R��(8D��!���3D519"3@+# �u;�(S?{�

���TrEr:�� R���SD|�8rEr��*1�D:\ :���K(3�/�$.x��*1�@#T(8DE�/?� �R�8��� ��q

[G��t ED�@���2�6z;�(*?+�e�/�j?+�3EDE�T%�(8Dv�*�!DE;+�!����;�(9��13�T��%m��r:r:��1�D5"&r�Hh4�f�(j��"j1*�T(�DE�*�ut`� Dv;m�j v@�%5@A��*�u�/�eDE;+��DE R�8(�D��!���3D5"�r

y��!q��v�^(K45,.fOt��LD�;)��� �}th"&�!���~"&r.(8D\# ��(jvDZd$�>'��(3 x�"&r.(*%+�6��"&r\t�;"&���8��� th�� R��DE(*�+�T��%e�|4�f-�p�V(9�T�#T'u,.�N�N�."0?�8 .(

�!�8(9���A�8 �� "��u"&rK���5'+�8(9 x����7��;�(*�19���!���SD�"&rNDE;+�K�8rEr�� 1*(31�'~"&rND�;+�h(S�SD��T1*;"$#��/��3ED��8 �(jR�T1K(*%����3D:�+DE(91* :�w��*�G�/�}Dp;�YDv :��(8Dv�!���SD�"&r

1*"&%���LDE�/?�mr�@��1�D�� "&�-�/�-�����e���3D��T(at�(&�"9P{��� �?�*�O(3r D��8 ���$�2th�*���{ �R�8�0W�>�8�����q.]I')13"&�3DE �(jED:�I(a ��819���SD}4Y,.f¡rE"9@�+�O�"

P����*rE� 19�T(3#C�*rEr:��1�DO"�rmHh4�f��TDE :(S�R���� E�K(j#C�*EDE :(9�&� "�#~�AqL�&W+d �K%��j(9' � "j �(3#��+ :"&%�*ED��8 �"&��¬�8��� �K%�p�&(S'0� t�;��� 13"��

(3�&�!�/�0� ED��� x�*� t��LDv;� :�T?�(jvDE�w%��!�T���r�"j oW ��th�*���mDv" d$X��*# �$�8 �#T'��!���"9�(S@{R(3#>th"0�!�������!�*(S� (S%��l���'+�8(9 x��V�!�8(9�

�!���"&�(S@{R�5�9@ :(�DE�T"&�KW�`'��(3 RR� �R�8�&U ��q9f|;0�5�&� rEr��8 R����13�5�T�!(S%�6�9DE�T�!�z�*#�(S�{R�*�K��w�19���!���"&�(S@{R��(&\th�*#T#A(&�DE :��(8D��!���3D�D�'&�{�

�2@��"9���A"���*�Q¥v± �+"9���A"07�*�&�N13"9@A# �z� :"9P(SP#T'!��c��#T(9�T�hD�;��"9PGR�� E?�*�>��� R1* :�7�(9��13� �*|P{�RDvth�*���hDE;+�ZDvth"KED�@�$� �6Sq3� D\�;"9@{#2�K(3# R"

HA

L author manuscript inserm

-00243083, version 1

¿dÃ

P�z�"*D:�*�`D�;�(8D�D�;�`�*rEr:��1�D."&rb1S;"�# �/��6vD:�� :(&R��DE ��8(�D��!���3Dbr�"& \y � ;0(&IP�*���e R�7�{"& �Dv�*�hDE">?�(3 v'erE"& .th"0�!���^�2P�@jDZ�"*DbrE"& \�!���A�

(31*1*"& :�$�T��%�DE"YDp;�*�T �y5�{"&�εU!ED�(8Dp@{�i9t�"0�!���Kth�LDE;K(*�

εUK(3#T# �*# ��;�(*?��T�$%!# �67\"jr�(�D� ��8(�D��!���3DN��r:r:��1�D �R�8��d ��q

f|;j@A��$t5;�8 R��(j�R"&�!��ED�@�$� �6��@�%�%+�6ED�D�;�(8D|�6EDv :"&%���>�V(S'e(91�D�(j\(5� ���?+���SD��T?�5(S%���3DNrE"& N�+��@ R"��$��%����� :(8Dv��"0�$�&Dp;�8 R�

� \� ��67���3DE#T'!�+"!��?�� �����19�.DE;�(8D�D�;�� \;"& ��!"&��5(31�D�.(j\(z :�*EDE"& :(�DE�w?�5(*%���3DN�/�!(3#T R�8(9�&'!����%����* �(8DE�*�`�+��@ :(9#�DE� ��@�*�+(3#LD�;"9@+%�;

�@1�;!(z;�'&�{"*Dv;�*�� .� �1* :�*�$��PA# ���E1*r�q�� �$���A��� �E��q&��c$��8 ��T�!���jD�(3#A�&(8Dv(h(9#/�"!�@����"& �D:ND�;+�67�5r:�T��$�T�&%$7�A�T����� 1*(�DE�w��%hDv;0(�DN�*EDE �"&%���

1*"9@{# �}P{�z��7@ :"9� �"*D:�*1�DE�/?��tz;���e(9�&�!�T�� ED��8 R�*�}P{��r:"& R��"& .(8D�D�;��hR(S�!�YDv�T�!�h(&\D�;�z���@+ :"�����%+����8 �(8DE�/?�hEDE�/�K@{#w@{��{P�@3D|�0"9D

t�;���K(3�&�!�/�� ED:�� :�*�`(3r D��� Et�(3 ��0.�E��*��r:"& N ���?+� ��th �TW�N������E��q

� �� � � � � � � ��� � ��� ����� � ���� � ����� ��� � � � � �� ��� � � � � � � � � � ��� � � ����� � � � � � � � ���� � �� �� �� ���

� � � $&�� ��,�&�,�����,��'&� #.�/$&� ��#%'���$ ���������,����� ����'&� /�'��� ���

_a"�ED�D�;�� :(S���@&DE� 1�DE ��T(3# .1*"&�+�3@+1�D:�*��D�"!�&(8Dv�5;�(*?��PA�*���!@+�(*P#T�.D�"K13"&��13#w@A���.DE;�(�D�Hh4.fO1*"9@# �!R�/%���Tr:�T1*(9�3DE#T'K� ���?���3D

D�;���$��?�*# "9��!���&Db"$rNy���"& .���*1* :��(j7���LD:�7��?�� :�LDv'�q&���� ���S�!� "�# "&%+��1*(9#GED�@A�&� �3��A�*��A�819�T(3# #T'hDv;����(3 �# � �� ."&��*��2PA�*r:"& R�u�8X�X0U��:�

;�(*?�>�&@�!�� R"9@{`# �T�!�LDE(�DE� "&�K�ER�*��r:"& � ���?+� ��th � X��8�z���8X�����W� �E��q ��(3 ��T(*P�T#T�LDE'm�T�uD�;�>��7@ R"3�A�'1�;"�#2"&%�T1*(3#�D:�*ED:z@AR�*�~(S��

D�;�*�T `# �T�!�LD:�*�o :(S�j%+�u(j}th�*# #.(&�D�;+�~#T(31��)"&rKEDE(*���&(3 ����T�3�*�o���T(*%��"�EDv� 1~1* ��LD:�� :�T(Cr:"& h�$���e���3D:�T(C(3 ��e(9�!"&�$%~DE;�^� :�T�+1*���+(3#

�;"& �Dv1*"&�!�T��%C�K(9��T��%��$��r�rE� 1�@#LD�(9��'�13"&�K�(9 :� R"&��PA�xDvth�*����ED�@+��� �**q�f|;�� R� (9 :�o�&@�!�� R"9@{m"*Dv;�8 �rE(31�DE"& x�t�;�T1*;�(3 R�

�"*D:���3DE�T(9#-19"&��r:"9@�+���8 R t�;�� 1*; ;�(*?�¬�"*D P{�*�����'ED����V(�DE� 1*(9# #T' 19"&�3DE :"�#T# �*� r:"& 7iO�!"0vD�EDp@��� �* �;"&t`�T��% (s;+�T%�;

;�RD:�� :"&%+����*�LDE'Cth�LD�;~ ���%0(9 :�KD�"^x@�P ���*1�D:z��(*%�*���*�&@1*(�DE� "&�C# ��?�*# ���a��q+_O"j ��!��A�819��r��T1*(3# #T'������� ��67��T?+�V�'��K�jDE"0�V(�D:"�#2"&%�'~�

(*�K�T�K�"& �Dv(*�3D�13"&��r�"3@+��&�T��%K?�(9 :�T(*P#2�6�0t�;�T1*;K;�(&\ :(* :��#T'`P{�*���!��?�(&#w@(8Dv�*�{qSy5�{"&�b�εU!EDE(�D�@{\� \(3# R"` :(* ��8#T'K%+�T?���K(3#LDE;�"9@+%�;!�LD

� �(S�~�T�K�A"j �DE(*�3DI%����RD:�T1> :� R�CrE(31�DE"& 5rE"& 5y��h��(*���u(S���/�SD��� :(31�Dv� "&�u;�(jz(3# R"� x�7�A"j �DE�*��t��LDv;~�N4�f�ED�(8D�@{ �R�8��l �xq+y�#LDv;"9@%�;

1�@ : ����3D`# "9��%�LD�@A�&�T��(3#5ED�@���2�6}(3 :�>PA�xD2D:�� h19"&�3DE :"&# #2�*�a(*�+�m�!"& R�e R"9P�@{vD:�\ E(*����"&�!�2�*(8DE�T"&�m� R��13#w@A���6zDE;+�u� �����3D���r��T1*(8DE� "0� "&r

"*DE;�� .�+"6D����3DE�T(3#N19"&��r:"9@+�0�$�8 R*q+���e�+ :"���A�*1�DE�T?�K19"&;"& �D�vD�@���� �*�"&��Hh4�fZ�$D�;�� :�K� 5(9#/�"^x�{�*19��r��T1`P�T(j*q+f|;0�zHh4�f)@{��* x�(3 ��

� :��r:�� R���3DE�T(3# #T'¡;��(&# Dp;�'���"0�������+ :�*���*����t��LDE; (�;��T%�; # ��?�*#m"&r)�*�9@1*(�DE� "&� (*���¡;�w%�;+�8 -�"�1*� "��*19"&�"&�!�T1�EDE(�D�@{�iu�w�

D�;���!��*#/?�35�+ :"*D:��1�D���?+�!rE(31�Dv"j R�(S%�(3�T�ED�1*"&%���LDE�/?�!���*19# �w��e�2;+�8(&#LD�;�'u@A��� �P�T(jR��q+yz�"*DE;�� �R"9@ :19�!"&r.P+��(&�� �DE;�(�D.th"0�!�*�

th�LD�;K�!�*�!"& �'K13"&�`�{#T(9�T�3D:\�K(*'K;�(*?+�.PA�*���K� :��r:�� R���SD��T(3# #w'K� ��6�1* :�wP{�*�zHh4�f �2P�T(j|P$'V�w����T1*(�DE� "&����q9MN"��\"�rN�@�P �7�81�D:\��\(3# R"

(m1*(�@{R�u"&r`13"&��19�8 �� �/� # "&�$%�LD�@{�&�T��(9#YED�@+��� �**qN���O(m :��13���3D` :��?�� ��th�5B$;�8 �th�/� ¤@§�³ ¬ �. ����"& �DE�*�~D�;�(�Dh�/� (*P+"3@&D�;�(9#�r`"&rh(9# #

# "&�&%�LD�@A�&�T��(3#�ED�@�$� �67�ND�;�CWdCD�" ����� "jr}th"&�!���)tz;"ar�(3�T# �*�~D�"a R�RD�@ v� r:"& K19"&%����LD:�T?+�!D:�*ED��T��%Oth�� R�~"�#2���8 R�\;�(*?+�m# �67

�*�9@{1*(�DE�T"&��|;0(9�m# "&th�� �_o_)B���1*"j ��6`(�D�P(j��*#��/��6�|(9���mth�� R�!�!"& R��# �T��*#/'^D�"uPA�>�"&��2@{7�8 R � d����q�,.# �w��21*(3#�D�;�� :(*�+��@jD��T1

DE :�T(9#/et��LDv;)��")13"9�3DE �"�#5%� :"9@��- �(3� R��DE;+�u� �"9P# ��� "&r># �8(9 E���T��%��8rEr��*1�D:>t�;�T1S; (9 :�CrE R� �3@A���3DK(3r Dv�8 > :�7�{�RDE�LD:�/?�~19"&%���LDE�/?{�

��?�(3#w@(8Dv� "&�uth�LD�;!Dv;�KR(9�!�YD��6vD:*q+4Y,\f)(* ��YDp;�`�!"�ED. :"9P�@GED�vD�@�&� �*���(3#LD�;"9@+%�;u%���+�8 �(3#T#T'~"&r���V(&#T#N��T�3�`(9��u�;"& �D|DE�8 ��!�

HA

L author manuscript inserm

-00243083, version 1

¿)Å

P�@jDKD�;��o?�(3# �2�j�LDv'�"&rVDp;�O��"9@�P{#2�6�2PA# �T���� m"9�A��� DE" �9@A�6�DE�T"&�kg�t`"&�!����rE :� �9@A���SD�#T'�%&@{�*��Dv;�~D�'&�A�O"�rKDE :��(8D��!���3D>D�;��'

:��13�*�T?+�*�0�I�9@{�!Dv"mP# �*�*�$�T��%)"& `�!���"9�(*@{7�uR'$�K�jDE"&� R�3R"&#w@jD�� "&�Gq � ��*����&(j#2�]¤@§T³ ¬ �. :�7�{"& �Dv�*�~D�;�(8Dzt�;+���ath"&�!���«th�8 R�

(j����*�o(8D5D�;�m����O"&r`(a����'��(3 `�+ :"*DE"&13"&# �����$� "&rYDv;���A# (31*�7PA"a%� �"3@$�)%&@{�*�7�*�~Dv;�!Dv'j�A�C"jr5DE R��(8D��!���3D5DE;+��' R�819�3�T?+�*�0�

1*"&�K�(9 :�*�5DE" �&d��EX����¡�w��DE;�I%� :"9@��!tz;"h ��819�*�T?�*�zHh4�f �:��� � ��q

����� � '&/#���� � � � ��� �. �/�,'��� ���# ' ��$ *"�,�&������� ��'&�"� /����� ���#

�.D�;+�8 N�$�67�T%&�h�+ :"9P{#2���e\(3 :�� :��#T(8DE�*�5DE"5DE;�I;�RD:�� R"&%����*�LDv'V"&rN�@�P �7�*1�D:\�w�13#w@���*�K�/�hHh4�faED�@�&� �*|th�LDv;V ���%0(9 :�5DE"`(*%�

(*���m;+�8(&#LDE;�|?�(3 v'��T��%)����r:�T��LDE�2"&�!"&r`�!���"9�(S@{R(9#�EDE(8Dp@{!���T��19#�@A���w��%)"& ��+"6D�� R���!���"9�(*@AR(3#Ith"&�!����:�\(S��uDE;+�!D�'���C"&r

�!���"&�(S@{R�*����(�D�@ E(3#|"j ��@+ E%��T1*(3# �ADv;�!#T(8D2DE�8 �%�/?�T�&%~�A�� E;�(*�{z�K"& R�K13"&�7�/vD:���3D� :�*�@{#LD:z�9@{�`DE"!Dv;�!�@A�������~(9���13"&�>�# �RD:�

# "��\"&rN�*EDE :"0%���V(91* :"��.�@$P ����1�D:.�E��*��r:"& N ���?0�2��tV ���3U�|��W����|�8��X�E��q�H`4.f~DE�w�!�T��%K� \(3# R"z� :"9PA# ���K(8D���1+g8Dp;���!�8(9�!�9@ :(�DE�T"&�

"&rh(S� 4Y,If�� }@{�@�(3#T#w')# �67hDp;0(S� �o�!"0�SDv;��TD�;�C# "&��%�*�DYD� ���(9#.P�*�/��%���H`�E_)BOt�;�T1S; #T(jED��*� d�q Wo'��(3 RR�ztY;+�8 R��(j`D�;�

(*?�� :(S%����9@ :(�DE�T"&�!"&rb"9P{7�8 v?�(8DE� "0�eED�@�&� �3I�/}�8�`'+�8(9 x��$(*����D�;�.DE�/�!�5P{�RDvth�*���hDE;+����c$�{"��@ ��5th�w���"0t�(*���D�;+�5�!���"$�(*@{��

(*%�*�+t5;�21�;^� Z� :"9P(SP#T'e1* ��LDE�T1*(3#Gr�"& b(zP{���+�8r���19�T(3#G19"&%����LD:�/?�h��r:r��81�D��A� I;�w%�;#T'>?0(9 :�T(*P+# �h�E"9P{7�� E?�(8DE�2"3�uED�@�$� �6IPA�*�T�&%e19# "����

DE"�Dv;�� ��8(9#19# �T��� 1*(9#��LD�@+(8DE�T"&�YDv;�(*�K4Y,IfCt�;�� :�.H`4�fm� |�"3D�(3�&�!�/�� EDE�� x�*�`�9@ :�/��%�Dp;�5�8(9 :#T'`�!���"&�(S@{R�\DE :(S�$�� Dv� "&����q3f|;��8 R�

(3 ��K(3# R"��j@+�!�� x"9@{`�&� rEr��8 R����13�*zth�LDv;~ R��%0(9 :�!Dv"!DE'&�A�!"&r�Hh4�f��TDp;0�}�!"& x�K R��13���3D5#T(3 v%�K4Y,If�"3�+#T'u@{7�*�~"& �(3#b,I�N�)t`� Dv;

1*"&�3D:�/�j@+"3@A._aF�yh�+t�;�� R�8(&\��(8Dp@ E(3#GEDv�8 �"�� �K;+"j v�!"&��*.(9 :��� :"9P(SP#T'>�!"j R��PA����*r:�T13�T(9#/�+�9@A���T�K�(9 �DE�T1�@#T(9 kDE"�Dp;�*�T b����EDE�w�1�D

��;�(3 v�V(913"&���T��RD���1^� :"9�A�8 �DE� �*����R�7U��:�\"& h�/�~D�;�u�� �9@A���13��"jrz(3�&�!�T�+�/vDE :(�DE�T"3�O"&r5� :"0%�6vD:�T� �pth"&�!���oth�LDE;O�6EDv :"&%���O(*���

1�'1*# �T1«� :"&%+�6ED��T��DE :��(8Dv�!���3Dut`�8 R�-�;"&t���DE"�PA�-7�T%���� r���1*(S�3D:#T'�# �*�O#T�T��*#T'�D:"� :�7�{"& �D~1*"0%���LDE�T?��R'��`�jD�"&�eO�@1�;�(j

1*"&�19���SDv :(8Dv��"9��DE;�(*��t�;+����(&�&�!�T�� ED��� :�*��th�LDE;�(*��"9���"�7�*��13"0�SD��T�&@"9@{CDE ��8(�DE�!���3D �R��UN� �:�}(j=th�*# #>(jorE"& a�*EDE �"3%+�*�

��13"9�3D:�/�j@A"9@{5(9�&�!�w�� EDE :(�DE�T"&��P�*�T��%~�@AR13�7�jDE�wPA# �YDv"e ��*�9@{19�K�N4�1*"9��13���3DE �(8DE�T"&��P�'u(*@&DE"& :��%&@{#T(�DE� "&� �R��U�W��E��qM|(jEDE#w'�+D�;��8 R�`�

(3# R"�?�(3 :�T(SP�T#��LDv'��/�eD�;�`� R�7�(3 �(8DE�T"9�5@A��*�~�v"& :(3#P¥v± ���(�DE1�;�ADp;�`�(3 ����3D:�� :(9#N�!"��$�!R;"& �D:��1�@jD DE�w��%Cr:�T xED��2�(j�z#T�w?�8 z�*r:r:��1�D:R�:�

t�;�T1*;a1*(S�a R�6�@+# Dz�T�a?�(9 :�T"9@{`�+;�(3 E�K(319"9��T��RD:�T1��+(8D DE�� E�*q|fN;��KDE �(*�R���� ��V(9#.(3�&�!�T�+�/vDE :(�DE�T"&�a"�r`�6EDv :(3�&�T"�#��/} :�7�{"& �DE�*�uD:"

� :"9?�2���h(> :(S��T�e �� ��K�T�C�6EDv :(3�&� "$#�7�� E@+��# ��?�*#�(9������(3 �#�'u19"&�EDE(*�3D�# ��?�*# ��<¨ �l¤���13"0�$vDE(*�3D��6EDv :(3�&�T"�# �E�3vDE :"9��K �(8DE�T"�R��"0?�8

D�;�C���3D:�T :��(*���#2��1*(�DE� "&�o�{�� :�2"��Aq �5 �(3#�(9�9�!�T�� EDE �(8DE�T"9��."&�aD�;�C"*D�;�� K;�(*�+�0�I :�*�@#LD:��w�O;�T%$;#w' ?�(9 :�T(*P#2�~��� E@+� # ��?A�*# �"&r

�6vDE :(9�j�2"�# ��(*��C# "&t`�8 �PA� "&(*?�(3� #T(SP�T# �LDE'~19"&�K�(9 :�*��th�LDE;m�6vD: �"3�+�!tz;"���`�A#T(j��V(�DE�T1!(31*1�@+�K@A#�(�DE�T"&�m13"9@{#T��P{�!�+��r:"$#��C;+�T%�;��

D�;�(*�K(3r DE�� N�*EDE �(3�&� "�#&DE E(*�R�$�8 ��K(3#+(3�&�!�T�+�/vDE :(�DE�T"3�!��(*�+�hW�$�ErE"�# �z;�T%$;�8 |����Dv;���V(9�K�K(j#T�T(9�h%+#�(S��&� �R��U���q

��� EDE�/�01�D�P{�2"�#T"&%�T1*(&#���r:r:��1�D:>"&r5Hh4�f�rE"& ��`@{#T(8Dv��"0�a;�(9?�u(3#T ��8(9�&'mP{�*���O :�7�{"& �DE�*�a�T�a R�*#T(8Dv��"0�~D:"CP R��(jEDz1*(*��13�� `"j

1*(3 ��j�T"&?�(&R1�@{#T(9 b"9@jDE1*"0�!�3��+�"*DE(SP#w'u�3@A�.D:"}?�(3 :�T(SP# �5�!��DE(SP"�#T� �*(�DE�T"&�Gq&fb �(*�R���� ��V(9#G�*EDE :(9�&� "�#G� �# �*�I;�(3 E�!r�@+#k"0�!�e(9 E���� x

"&rb1*(9 :�&� "&?�(j�1�@#T(3 \ :� ��hD�;�(*��"& :(3#��6vDE :(9�j�T"�#���"& Z,I�N�N�|t�;�� 1�;!(31�DE�/?0(�D:�*\P+# "�"��K19"j(9%&@#T(8Dv� "&��+�T��1* R�8(&R�6�,)45��(31�DE�/?�5Fk �"*DE�*�T�

HA

L author manuscript inserm

-00243083, version 1

¿ �

�E,.4�FG��(S���C�!"���� rE� �*K"*Dv;�� 5P� "�#2"&%�� 1*(3#\�K(3 v��8 RK�@1�;m(j5DE ��w%0#/'13�� :� �$�e"& �M ��M�# ��?�*# �|"j z(3# R"CM ��M��(9 �DE�T1*# ����T�3� �R��U�U�

��U � ��q$fN;�� �t�(j�(3# R"� R�819���SD�#w'~�@%$%�6vD:�*�>P�'u(>�h@A#LDE�T13���3DE R�`;"����LDE(9# �2P(j7�*��1*(jR�3��19"&�3DE :"&#NED�@A�9'ut�;�T1*;~�;"&th�*�KD�;�(�D."& :(3#

P�@jD��0"*D�DE :(S�$����8 ��K(3#A�N4�fmt�(jI(3�R"&1*�T(8D��*�`th�LDE;!(`U��rE"&# �>�T��1* x��(j����T�! :� ���"&r�?���"9@{|D�;� x"0�hPA"����KPA"�#T�/����T�!1�@+ : :���3D�@{R�� x

�R��UX��q9_a"& ��*"&?�� x�9D�;��;�(3 E�Kr�@A#A�*rEr:�*1�D�"&r�� R"3%+�3EDE�T���+�*��A�*1*��(9# #T'!R'&�3Dv;�xD��T1����� R��?�(�DE�T?�*��<¤�� Â��+_aF�y���;�(j|PA�*���K x�7�"& �Dv�*�KrE"j

1*(3 ��j�T"&?�(&R1�@{#T(9 N :� ��!�R�8d$���\�8d�� ��q&4���%�(3 :�&�T�$%KP :��(jED|1*(*��13�* R��_oFAy �C"& :(3#A�|4�fot�(j\ :�7�"& �D��*��DE">�T��1* x��(j��5�!�LD:"*D���1z(318Dv��?+� Dv'

�T�m���A�LD�;�*# �T(3#\13�*#T# `�T�u�A"�EDv�!���"9�(*@{�(3#�P ��8(&ED �R�8d&W �It�;�* :��(j�D�;�� z�!�LD:"*D���1>(31�DE�/?�LD�'~t�(&`���81* R��(jR�*��t�;���C� �"&%�*ED:�� R"9�{�

t�(j�(3�����*�oD:"aDv :(*�R�$�8 ��K(j#z�N4�f �R�8d$���q.f|;0�m R��13���3Du�$(8D�(O"jr`DE;+�a_a�2#�#2� "&�)��"&�!����BjDp@�&'��T� Dv;� � ���w��$��1*(�D:�*��(*�

�T��1* R�8(&R�*�a ��/x� t`� Dp; �*EDE �"&%����2� R"9%�3EDE(S%��� 19"&�`�(3 ��*�~DE"O�*EDE :"9%���)"&�+#T'�\th�LD�;O?�� E')#T�LD DE# ��?�(3 :�T(�DE�T"&�aPA�xDvth�*���)��{�*1*�2rE� 1

�6vDE :"&%+���$�(S��`� :"0%�6vDE(*%��� �R�8d&U��:�$P�@jD\�LDb�;"9@# �KPA�z�!�*�3DE� "&�+�*�hDv;0(�DGD�;+��13"&�`�A# �xD��z;� EDE"& E'u"&rN;+"j ��!"&��(9#DE ��8(�DE�!���3D|t�(j

�"*D�1*"0�$7� ���� R�*�u�T�eDp;� hEDp@�&'��t�;�T1S;~"&�#T'Cr:"&1�@{7�*�~"&��D�;�K�!"�ED� :�*19���3DbDE ��8(�D��!���3DbDv(*����Gq�����DE;�K"*Dv;�� �;�(S����AD�;�Kr��� RED

[G �����1*;C� �"0x�{�*1�DE�/?�uED�@�&'a�/�mt�;�� 1*; �j��� "jr.Dv;�e���8l�dC�+"0vDE�!���"9�(S@{R(9#Nth"0�!���ath�� R�! R�819�*�T?�T�$%�(u19"&�`P{�T��(�DE� "&�a"&r5(

DE E(*�R�$�8 ��K(3#N�3EDv :(3�&�T"�#�%+�*#k(S���(K� �"&%�*EDE�T�C"6Dv;�� bD�;�(S�^_OF�y��&� ���"*D��;�"&t�(*�$'~��?� ������19�!"&r��T��1* ��8(&��K�T��P ��8(&ED.1*(S�019�8

:� ��~��?+���^(9r DE�� YX>'��(3 R5"&rNDE :��(8Dp�!���SD �R�8d�d�\t�;+�8 R��(j5(S�^�/�01* R��(jR�K�/�eP+ :��(jED.1*(S��13�� .t�(j5"9P{��8 �?�*�u��(3 �#w'^(9r DE�� bDE ��8(�D��!���jD

th�LD�;!,.�N� �u_mF�y ��4�4��*q W����,I� � � ���3qL�������3q d�X&�G(9rE�8 |(5�V�*(S�VrE"$#�#2"&tV�2@��!"&rNdAq W`'��(3 x�� �R�7Wd�E��q

f|;0��(j�&���LD�� "&�O"�r��+ :"&%�*EDE�/� �K(9'O;0(9?��;�(3�o(m�!"����Trv'�T��%)�*rEr:�*1�D`"&�mDE;+�u :� �� "&rK����?+�*# "9�{�T�$% �$���!���jD:�T(CP�*1*(S@{R�

� :"9%�*ED��T���.�*��A�*1*�T(3# #T'O_aF�yh�\;�(*?+�uPA�*��� R�7�{"& �Dv�*�~D�"a(8D2DE���&@(8DE�C"& K13"9@+�SD��� :(31�D5D�;��m��rEr:�*1�D:^"jrK�*EDE �"&%���O(*��=�{"��R�wP#T'

�T��1* R�8(&R�YDp;�h �� R�u"&rND�;� R"&�hPA"����KPA"�#T� 1K��?���3D: �R��d���:��"& .13(3 ��&��"0?0(&R1�@#T(3 .�$�/7��(j7���R�8d�l��q9���LDv;e R��%�(3 ��hDE"��+��@ �"9� :"*D��*1�DE�T?�

�*rEr:�*1�D:7�&D�;�� :��� �(3# R">(31*1�@+�h@A#T(8DE�T�$%e��?� �$���019��r:"& \(h�$��r�r:�� :���3D\�*rEr:�*1�D�P{�RDEt`�*���e_aF�y�(9��!"*D�;�� |� :"&%+�3EDE�T�*q&F� :"9%�*ED:�* �"9�{�

;�(jzP�*���a ����A"& �DE�*��¨l¦�¥@¨»§l£}«uDE"uPA�>��7@ :"9� R"*D:��1�DE�T?+�e(9# "&���"& ztY;+���a(3�&�!�T�+�/vD:�� :�*�Cth�LDv;a�6vDE :(9�j�2"�#Z��(9#LDE;�"9@%$;^D�"~(�# �67���

����%� R�*�VDp;0(9�a�*EDE �(3�&� "�#.(9#�"0��*�5t�;�� R�8(&K_oFAy t�(j}(*�a�w��*rEr:�*1�Dv�T?����7@ �"3�+ :"*D:�*1�Dv(*�3D�(S�0�o��?���a13"0�h�A# �RD:�*#T'a(S�3DE(*%"0��T�3�*�

�6vDE :"&%+���{���T��9@19�*����7@ :"9� �"6D��*1�DE� "0��tz;����13"���(3�&�!�/�� ED:�* ��*� �R�8d �j�m�8d$X��q�f|;��/ �/o(9#/�" x@�%�%�*ED��*��P+'�(��+ :"����*1�DE�/?{�

"9P{��� E?�(�DE� "&��(3#AED�@+�&'V�/�Kt�;�� 1*;`th"&�!���hDE(S��T�&%!,.�N� �u_oF+y �13"& :�*�K��w%��+��r��T1*(3�3DE#/'V# "0th�8 |�T�K%#T"9P(3#+13"&%$��LDE�T?�5r�@��1�Dv� "&��T�&%�

(*P{vD� E(91�DG ��8(&R"&���T��%K(*�+�`?�8 vP(3#+rE#w@{����1S'�Dv;�(*�`P"*DE;K���?+�8 �@AR�8 R\(*���`�N4�fo"3��#T'`@{7�8 R\(3r DE�� N(5W�2'� GD� :��(8Dp�!���SD �R�������qSHV���19�6�

D�;�� R�h(9 :�KR��?�� :(3#�# �/��6z"&r���?�2�����13�5DE"u�@+%�%�*EDND�;�(�D\Hh4�f«�� :�*R1* :�wPA�*���T�!DE;� �KqwBkqA��"& :(9#N,.�N�O(*����_aF�y��.13"9@{#2�!P+�K# �67

��7@ :"9� �"6D��*1�DE�T?+�e�E"& 5�!"& ��K;�(3 ��Kr�@# �bDp;0(9�eDp;0(�D.�+ :�*R1* :�wPA�*�~�T�C��@ :"9�A�K(*��C�*��{�*19�T(3# #T'C�T�~[G �(*��13�!�TDv :(*�R�$�8 ��K(j#\�*ED: �(3�&�T"�#

(*���O��(8Dp@ E(3#I� :"9%�3ED��� :"&����K :��%�(9 :���w��%)?�(9 :�T"9@{�1*# �T�+��1*(9#�"9@jDE19"&�!�3��E��*�mr�"j K ���?� ��t �R�8��� �E��qNy`#�#z"jr�Dp;�67���{"��/�SD�K;�(9?�

@����"9@�P&D:����#T'uD:"�PA�hDE(S������/�SD�"C(31*1*"9@�3D�PA�8r�"& x�>�& :(*t`�T�&%a(*�&'a����r:�T��LDE�/?��13"9�13#w@{�� "&�m :��%�(3 ��j�/��%^Dv;����r:r:��1�D:`"�r�Hh4�f�"9�

1*"&%���LDE�/?��r�@+��1�D:� "0�0�/��%V(S��`�����e���3D���(+q

HA

L author manuscript inserm

-00243083, version 1

¿ �

� � � ��������������� � ��������� ��� � � ��� �� ������� �����!������ � � � � �� ����� � �

_a(S�&' �*EDE �"&%����� R�*#T(8DE�*���&� ���(j7�67�K�T��13#w@A�&�T��%�P+ :��(jEDC1*(*��19�8 R�K(*��� �{"�#/'019� EDE�T1�"&?�(3 ���(S� �'$��& :"&�!�*�>�����"&�!��DE ��T(3#

1*(*��13�� 5(*���C�����"&�!��DE �� "�R� �(9 :��DE ��8(�DE�*��th�LDv;~�& E@�%��{"��7�3�R�w��%C(*�3D:�2�6EDv :"&%����� 1>(31�DE�w?�LDv'��t�;�T1*;C�K(*'~(9#/7"C�8# �T19� D��!"�ED�"&r

D�;�!R(S�!�e�'$�K�jDE"&�ez(j�D�;�"���K19"&�K�!"&�#T'a�;�(3 ��*��P+'uth"&�!���mt��LDE;C# "&t �6EDv :"&%���m�7c��{"��@+ x� � l$X��qAf|;0�� R�`;�(j�D�;&@{5P+�*�*�

R"&�!�¡13"&��19�8 ���Dp;0(�D�(*�3DE� �3EDv :"9%����DE :��(8Dv�!���3D�r:"& �P :��(jvD-1*(S��13�� �� :��?���3DE�2"&�s�V(9'�PA��(&�R"�1*�T(8D��*�¬th�LD�;�13"&%$��LDE�T?�

�&'Rr�@+�01�D��T"&�GqNB$'��3DE;+�xD��T13���"0��;"& ��!"&��(3#\13"&�K�A"9@������IB�N4�_ ��;0(S?��KPA�*��� ����?�*#2"3�A�*��DE;�(8D51*"9@A# �C;�(*?���*EDE �"&%���m(3%+"&���/vD

(*���O(9�SDv(*%"9�� EDK(91�DE� "&���T�-�*EDE �"&%����� R�6��A"9���T?+�uDE� ��@A�6*q\f|;��uD�th"«�!"0vDKth�2���*#T') :�*19"&%���� �3�*��B+�N4�_O�bDv(*�K"3cA�Tr:���-(S��

:(9#�"9c�Tr�����6�k;0(S?�K�*EDE :"0%�����(3%�"&�+�/vD\� :"9�A�8 �DE� �*5"&��P"&�+�h(S���# �w�� ��5(*�+�u�6vDE :"&%+���$��(S�3DE(*%"0�� ED.�*rEr:��1�D:z"9�eP+ :��(jED:��t5;�� R�8(&

:(9#�"9c�Tr�����`@��# �/���DE(*�!"9cA�Tr:�����;�(jz�6vDE :"9%���{��(S�3DE(*%"0�� ED��*rEr��81�D��"&�!Dv;�z@jD:�� E@A �R�8�&W ��q+f|;��*�� 5��rEr:�*1�D:z"&��P �(3�w�u;�(*?�}P�*���

:��?�� ��th�*�># ��(j�&�T�$%hDE"�DE;+�Y19"&��13#w@{R�2"&��Dv;�(8DADE(S�!"9c{�Tr:���>�V(9'!(S�SDv(*%"&��� �9�Y7"&�!��"�rADv;��P{���+�*rE� 1*�T(3#G��r:r��81�D�."�rN�*EDE �"&%����"&��Dv;�

,N<�BO��� D��+"6Dv(*P#T'm(31�D�`(j`(���@+ :���6vDE :(9�j�T"�#.(S�3DE(*%"0�0� ED�th�LD�;a :�*��A�*1�D.DE"a7�8 �"6D�"&��� E%+��1^�!�*1*;�(9�� R�!R�:�|t�;�� R�8(&` :(9#�"0c�Tr:���

�V(9'u�7c{�� �D.�*EDE �"&%����E#2�T��`�*rEr:�*1�D:�"&�u1*;�"�#2�T��� E%�T1�DE �(*���!������"0� �R�������q�f|;��h(S�3DE�����N4��8rEr��*1�Db� �(3# 7"e�@$���{"& �DE�*�KP+'VDv;�`rE(31�D

D�;�(8D�th"0�!���ath�LD�;CP R�8(&ED51*(*��19�8 �Dv :��(8DE�*�Cth�LDv;^Dv(*�!"9c{�Tr��*�m13"&�>�!"&�#T'm R���A"& �D�?�(jR"0�!"6D�"& h�'��`�jD�"&�e��|�!"�"&�m�T�EDv(*P�T# �LDv'$�

(*���`13"&%����LD��T?�5�9'$7r�@��1�Dv� "&�Gq

���e(!vD�@�9'e(9�T�!�*��(8D\1*"&�K�(9 :�w��%e19"&%���LDE�/?��r�@+�01�D�� "&�+���$%^�/� ���8�$�Kt`"&�!���~��(*%�*��d�l�El$d&�:�A#T�LD D�# �h�&� rEr��8 R����13��P{�RDEt`�*�*�

th"&�!����t�;"«;�(3�o@{7�*�aDE(*�!"9cA�Tr:���-r�"j >r:�T?+�C'�8(9 x�(S��O���?+�8 }@{��� x^th�� R�~ R�7�{"& �Dv�*�)"&� D�;� R�*�m13"0%���� D��T?��D��6ED�~�v1*# "&1*�

�& :(*t��T�$%$�z13"9�+'�T��%�(OPA"9c��& :(St��/��%�(*�����(9 : E(8Dv��?+�Ot� :�LDE�T��%�� �R���&U ��q5,\@ � :�7�SD>@A��� x�;0(9�-(���T%$�0�2rE� 1*(*�3DE#T'�#2"&th�� u�!��(&�

1*"&�K�A# ��cA�LD�'~R13"& ��K"&�#T'u"&�!D�;�`��(9 : E(8Dv��?+�`t� ��LDE�T��%!DE(&���G�w��$��1*(�DE�T��%!D�;�(�D.1�@ E :���3D\@AR�K"&rNDE(*�!"9cA��r����u�K(3'u(9�3?+�8 R��*#T'C�*rEr:��1�D

13�� �DE(9�w�a13"9%���LD���?+�ur�@��1�DE�2"&�K�T�a(C :�7?�� x7��P+# ��t�(9' R�T��13�!Dp;�8 R�>t�(jV�"m���Tr:r��8 R����13�>PA�xDvth�*���m�(&ED5@{��8 RK(*���C�"0�$�p@{R�� x*q

,\@ E ����3D�@{7�� x\(3# 7"h R�7�{"& �DE�*�K�!"& R�5rE :� �9@{���3D�#T'K13"&��@A#LDE�T��%KD�;�*�T ���;�'7�T13�T(*�.r�"& N�!���!"& �'K� :"9P#2���eND�;�(9�K�"&�&@{7�8 R*q ��7�T�&%

(uP+(�D DE�� E' "&rz��7@ :"9�{�'�1*;"�#2"&%�� 1*(3#ND��6vD:��|?�(*����(9� ¤@§T³ ¬ �. :�7�"& �D��*�m(~�$"07�*�E�����A��������3D`���*# �RD:�� :�2"3@A!��r:r��81�D`"&�a19"&%���LDE�/?{�

r�@���1�D:�2"&�e�T��th"0�!���ut�;"};0(9?�z :�*13�*�/?�*�eEDv(*���&(3 :��"& \;��T%�;u��"�7�6�"�r\(3� ��@?�(S�SD\1S;���!"3Dv;�8 �(*��'>�#w@{\DE(*�!"9cA�Tr:���e19"&�!�+(3 :���

DE"K13"0�SDv :"&# ��$P�@jD|�T�hD�;�5(*PA�����13�z"jr|(YDE(S�!"9c{�Tr:���!(9 E����t`� Dv;"9@jD|(3� ��@?�(*�3D|1*;���!"3Dv;�� :(S��'��b"9���1*(S���"*DN19"&��13#w@A���.DE;�(8D�D�;�� :�

� 5(e��+�81*�Tr:�21K�*rEr:�*1�D\th�LD�;!DE(9�!"9c�Tr:��� �R�8��d��q$y��"*D�;+�8 �1* :"�87�ER�*1�DE� "&��(9#�vD�@�&'urE(3�T# �*�KD�"����xD��*1�D.(S��'~R�T%���� rE� 1*(S�3D.���*# �RD:�9 :�T"9@{

�*rEr:�*1�D:�"&��1*"&%���LDE�/?�hr�@$�1�DE� "&�+�T��%Gq�fN(S�!"9c�Tr:�����V(9'u�w�erE(&1�D|;�(*?�`���*# �RD:�� :�2"3@A5�8rEr��*1�D:�"&�e19"&%����LD:�/?��r�@+�01�D�� "9�^x�{��13�Tr:�T1*(9# #T'

(8D+D�;�IP��%�T�����T�$%!"jrAD�;+�8 �(*��'K(*���K�Tr�;�T%�;K��"�R(*%+�6\(9 :�.@AR�*�!�ER�*��r�"& N :�7?� ��t �R�8����E��q

���LDv;� :��%�(3 ��)DE"� :(9#�"9cA�Tr:����*�`(9��4Y,.f¬t��LD�;���U���{"�EDv�!���"9�(S@{R(3#`t`"&�!���� R�7�{"& �Dv�*���"�19"&�R� ED:���3DC��r:r:��1�DC"&�

1*"&%���LDE�/?��r�@+�1�DE� "0��T�&%h@A��w��%K(5P(�D DE�� E'K"jr�19"&�K��@jD��8 ��T�3�*�5D:�*ED:��0�"& N"9�K�!"�"����$13"&�`�(9 :�*�5D:"z�#T(319��PA"h"0?�8 |"&���'��(3 ��R�8�$���q

fN;��u#T(9 E%�KDE ���(9#."&r� :(9#�"9cA�Tr:����u�/� l��wUl �~"�ED��*"9�"& R"6Dv��1^�{"vD��!���"9�(*@AR(3#\th"0�!��� t�(&K1*"&�K�A# �RD:�*�o"3?+�8 5DE;� ��*��'��(3 x>�TD�;�

HA

L author manuscript inserm

-00243083, version 1

¿ �

_m@#LDE�w�A# ����@&DE13"&�!�*5"&r\4�(3#T"9cA��r�����`�N?�(3#w@(�DE�T"&� �T_ �54����NDE :�T(3#T��q ���VD�;+�hR�wcu13"&%&��LD��T?��D��6vD:I��8 �rE"& :�!�*�����!��(3��13"&%$��LDE�T?�

R1*"& R�6I�T�K� :"0?�*�!R# �T%$;SDv#T'e"&?+�8 �D�;�.Dv;0 ��*�5'��(3 R*q�,."9�`�(3 ��*��DE"�DE;+���A#T(319��P"}%� :"9@��{�$th"0�!���e(j7R�T%���*��Dv"K :(3#T"9cA��r�����5;�(3�K(

R#T�T%�;3D�#T'e# "0th�8 . �� R�u"&r.����?�*# "9�A�T��%�13"&%����LD��T?�`���*1*# �T��`"&�u(8D2DE���3D��T"&�e(9��>?�� EP(9#��!���!"j �'KD:�*ED:�"&�#/' �R�8��l ��q��E�`� R"&?���!���&D

�T�a?+�8 vP(3#I�!���!"j �'oth�LD�;a :(9#�"9cA�Tr:�����;�(jK(9# R"CP{�*���a R�7�"� �DE�8�o�T�~Dvth"aR�K(3#2# �8 KED�@+�j�2�3��\"&��u�/�019#w@{�&�T��%m�A"�EDv�!���"9�{(S@{�(3#

th"&�!���Kth�LDv;"9@jD�y���(*��5D�;��"*DE;�� ��"�EDv�!���"9�(S@{R(3#$th"&�!���Kt`� Dv;`y � �R��� � ��q

Hh���19�YDv(3�!"9cA�Tr:���C�V(S'~;�(*?+�!�*EDE :"0%�����(*�3DE(*%+"&�� ED��*rEr:��1�Dx5"0�}Dv;�`P �(3�w���t�;�� R�8(&5 :(9#T"3c+��r����~�K(9'u;�(*?�>�6vDE :"&%+���{�

(*%�"&�� EDZ� :"9�A�8 �DE� �**q+fN;�*7�K�j(�DE(! �� �9@�T x�K1*"0�rE�T :�K(8Dv� "&��P'�th�*# # �E���3��T%���*�u#2"&��%�LD�@�$�T��(3#bEDp@��� �*��+DE(*���T�$%~�T�3D:"�(91*13"9@�3DNDv;�

�!��DE;+"j�$"�# "&%�T1*(9#)# �T�!�LDE(�DE� "9���T� �!"ED�� ���?� "9@{�vD�@��� �**qC[G"& ��7c(9�h�#2�6�CDv;�  :�*#T(8Dv�T?�¡13"&�3DE ���P$@jDE� "&� "&r�(j� �R@$?0(S�3D

1�;���!"3Dv;�� :(*�$'$��(9� ��@+?�(*�3D.;+"j ��K"&��(3#GDp;�8 �(*��'~�<¨ �l¤��\B�|4�_ P�'~�LD:7��#�r��.(*���1S;���!"3Dv;�8 �(*��'�v���+�3@A13�*�^�!���"&�(S@{R�` x���!(9�w�}D�"

P����c��# "& R�*�C(jzth�*# #\(j}"*D�;�� h1*"&�+r:"9@�����/��%�rE(91�D:"& R` :��#�(*DE�*��D�"~r����!(3# �u�@{�13�7�jD:�wP�2# �LD�'��[¨ �l¤��b(S%�*�N�*�9@A1*(8DE�T"&��\���7� R�3�R�w?�

�'��`�jD�"&�V(�D:"&# "0%�' �a� �R�8��� ��q+y�#T(3 v%0�`yz�!�* :� 1*(S�^(S��u,.(S�(3�&�T(*�~ED�@A�9'�Dv;�K,."��B+fNy�4�ED�@�9'~��BjD�@+�&'~"&r.fb(S�!"9c{�Tr:����y���

4�(9#�"9c�Tr����E13"0%���� D�� "&���.� �1�@ : ����3D�#T'u�T�&?�3EDE�/%0(�DE�T��%KD�;�K��r:r��*1�D:�"jr�DE(9�!"9c� r����e(*�+�! :(9#T"3cA�Tr:���~"9�u13"0%���� D�� "&���T�eW+�����>th"0�!�*�

(*%�*�K��dz'���(3 x\"& N"9?�� N(S�0�`t��LDv;h;�/%�;hP+ :��(jED�1*(S�019�8 | :� ��Gq

[G�w��(3#2#T'�m%+"&��(3��"*DE �"3�A�T�� R�8#2�8(&��T�&% ;�"j ��!"&�+��� � ��4.H`��(*%�"&�+�/vD:�t�;�T1S; (3 ���@{7�*� D:" DE ��8(�D�PA���0�/%�� 1*;� �"&��� 1

%�'����13"$# "&%�T1*(3#���� �"& ����8 R��@+1�;e(jI�����"&�!��Dv :� "�R� .(S��`@jD��8 R�T�+�Yr��wP :"��2�0�"& \�K'"&�K(j�+"& |� :���!���AEDE E@+(3#G�'��+�j �"&�!�*�A�@��+� :�*�

"&?�(3 ���(S�-r�@��1�Dv� "&�-(S��aDv;j@A�;�(*?+�a;$'j�+"�E�*EDE �"&%����T1 �� ���O�8r�r:��1�D:���?�(&R"&�!"3D�"& ^x'��h�&D:"&�!����!"�"����&�/7"& :���� x7�5(*���«P"&��

�����!�T��� :(9# �T�*(8DE�2"&�GqKfb���`�A"j �(3 v'�1*"&%&��LD:�/?������13#2�T���;�(&O(3# R"�PA�*���� ����A"& �D��8�Aq}yz«(*� �7c(*�`�{#2�6�KDp;� � ��4IH (S%"&�� ED:�

# �7@�� :"$# �T���a(913�RDE(8D��a�����+"6Du�E��q l$d��K%���w�3DE �(*�`@{R1�@A#�(9 :#w'����?+�8 �'�th�*�����:�zt�(jm�;�"&tz� D�"-�$�*1* :��(j7�a?+�8 vP(3#z�!���!"� �'�(S��

# ��(3 E���T�$%��2P�@jD��"*DI?� �@(9#N�!���!"� �'���(9r DE�� e�7WCth�*���`"jr\DE;+�8 �(*��'~�/�~'"9@+��%��;��(&# Dp;�'~t`"&�!���{��19"&�h�+(3 :�*�>D:"��+ :�RDE R�8(�D��!���jD

P(j��8# �/���t�;���hDv;�*�T N"&?�(3 �� �6\r�@+��1�D:�T"&�+�*�K�"& ��V(9#T#T'Gq3_O"�"&�!R1*"& R�6\(9# �"K�T��1* R��(jR�*�K�9@ ��T��%�DE;�5"&?�(9 :�T(*�!�@����+ :�*���2"3�K�+;�(jR�*�

P�@jD�D�;��/et�(&`�"*D`1*# �T�+��1*(9# #T' 7�T%���� rE� 1*(S�3D�(9��� �$���o�"*D`�T��r:#w@A����13�u19"&%���LDE�T?+�~R13"& R�*!7��%$��Tr:�T1*(9�SDv#T'Gq�fN;� }�!�*�!"& �' �$�*rE� 1*�LD

1*"9@{# �}P{��� :��?���3D��*�e��(&�th�� :��Dv;�h�'��`�jD:"0�e�"$rN;�'&�A"��*EDE :"0%���� R�!�|P�'�13"&�1�@+ : :�7�3D��:(&�����2P(31������6EDv :"&%����(3�&�!�/�� EDE :(�DE�T"&�

�E,.�N�a��q �0Wdz�h%!r�"& �5th�*���R���R�8�$X��q3f|;�� .�@�%�%�*ED:�Dp;0(�D��6vDE :"&%+���K�V(9'K;�*#w�hD�"`�V(9�T�3DE(3�T�K?+�8 vP(3#+�!���!"& �'!�T�Kth"&�!�S�V(S��

D�;�(8D:�0(8D�#T�8(&ED��w��Dp;�Y�;"& �DADE�� E�!�$13"&%&��LD��T?��1S;�(*��%�*.�9@A�bDE"K�*EDE �"&%���K����� ��T?�(8DE�T"&�K13"9@A# ��PA�� ���?�� xR�wPA# ��t��LDv;V�|4�fm�� �"3?+� ���*�

D�;�����*#T(3'`P�RDEt`�*���!13"9%���LD���?+�Y�'��K�jDE"&��"&�7�xD�(S��5DE :��(8D��!���3D�� |�"*DADE"�"`# "&�$%�q

½B¦ ±#¶>¯�¯³R£µÁG�ztY;+�8 R��(jm( ���@+ :"9� :"*D��81�D��T?�O �"j#2�)r:"& C�6EDv :"9%�����!�/%�;3D�PA�)��c$�{��1�D:�*���5D�;�� =;�(jC��"*Du(&C'�RD�P+�*�*�

(3��� �9@(�DE�*#w'e�����!"0�$vDE :(�DE�*�Aqj,I"&�K�(3 ��w��%!13"&%&��LD��T?�I�{�� :r�"j v�V(9��13�5(91* :"��."& �PA�RDEth�*���!19"&����LDE�2"&�\(j�R"&19��(�D:���Kt`� Dp;e��� rEr��8 ����3D

;"& ��!"&��K�7c��{"��@+ :�*�kx@1�;u(j���;�(&R�6�"jrNDv;�`�!���EDE v@(3#�1�'1*#2�6���E�@ v%�� 1*(3#T�.�!���+"3�+(*@{7�h(S��>?�(3 :�T"9@{z��cA"&%���+"3@A�;"& E�!"&��(&#

HA

L author manuscript inserm

-00243083, version 1

¿ �

�*rEr:�*1�DE"& R��A�T��19#�@A�&�T��%��N4�f.��B+�N4._�"& � ��4.H�(*%"0�� ED:����@�%�%�*ED:�(`�"��7�wP# �K��r:r��81�D\(8D\# ��(jvD."&��?�� EP(9#G�!���!"$ E'�+P+@jD�D�;��

;�(jI�"*D|P{�*���u13"0�019#w@{��/?�*#w'~�����!"&�EDE �(8DE�*�Aq ���!D�;�K"*D�;�� .;�(*�+�0���LD\� YvD:�T# #�@��13�� �Dv(3�T��(j\DE">t�;�RDE;+�8 NDv;�� x�`� �(`� :��?���3DE�/?{�

�*rEr:�*1�D5"9�a�����!���jDv��(��T����A�LD:�>"jr.D�;+�!�&@+�!�8 R"9@{`ED�@�$� �6`(9# :��(3�0'u�{�� :r�"& :�!�*�Aq�����`� R"9P(SP# �!�;"& �D:��1*"&�!�/��%m;�(j�P{�*���eDv;�

rE"�1�@{�"&�u#T(8D��6�v"&���RD.���!���"0�(*@{�(3#T�N;+"j ��!"&��(9#G1*;�(S��%�3�¨ �l¤��G(�Db(5DE�T�!�zt�;���!D�;+�`���@+ :"�����%+����8 �(8DE�/?�5� �"�13�*��;�(j�(9#� ��8(9�&'

P��%&@��>(*����t`� Dv;"9@jDuDv(*���T�&%��T�3D�"�(91*1*"9@�3Dm�T�+���T?�T�9@(3#�#��2r:�*�TD:�T�!����c$�{"��@ �� Dv"�;"& ��!"&��(3#>?�(3 :�T(SP� #T�LDE'Gq`_a(S�j'¡"�ruD�;�

�T��13"&�R� ED����1*� �*� :�7�{"& �D:�*�>�T�hDE;+��# �LD:�� :(�D�@ ��5�V(S'!PA���9@{��D:"`D�;��rE(91�DGDv;0(�D�th"0�!���^�$"!�+"6D|(3 � :�w?�5(8D|�!���"9�(S@{���th�LDE;�� �3@+(3#

:� ���"�rb19"&%����LD:�/?�h�$�*1*# �T��*�A"& �� �9@(9#k�@AR13�7�jDE�wPA� #T� Dv'VD�"hDp;�h�*rEr��*1�D:�"&rNHh4�fYq&f|;��8 R��� ��+"&t R"0�!�K��?� �����19��D�"e�@�%$%�3ED�D�;�

��cA� ED����019��"&rm?&@{#/��8 �(*P#2�-r����V(&# ���@�P�%� �"3@$�{O(8D�;0�/%�;� :� ���"&ra�$��?�*# "9�{�/��%����@ :"��2�{�'�1*;�T(�DE :�T1��&� �"& :�$�8 RO(8Dax�0�*1*�2rE� 1

�!"&�e���3D:����KDE;+�*�� . ����+ :"��9@1�DE�/?�h#2��r��6�u¤�� Â��At5;����(!�& :(&EDE�T1h�& �"3�u�T�u�*EDE �"&%���5"&1*1�@ x7�G�@1�;�(j�(�D�D�;��5� ����!���{EDE v@(3#���;�(jR�

"&rkDv;�`1*'�13# �*�A(9r D:�� \�"�ED��+(3 �Dp@��}��"& .(8D�D�;����A�� :�T�!���"0�(*@{������ :�2"��Aq3� ;� # ��Dv;�`� �����3D���r��T1*(8DE� "0�^"&r�DE;+�/5�@$P{R�RD."�r\;"& E�!"0��6�

R�����LDE�/?� �@$P ����1�D:�th"9@# �«�{�� ��!� DKDp;�m� ���?���3D:�/?�m@{7�O"&re(oDE(3�T#T"& x�*�OD�;�� :(S��'�P(jR�*��"0� ED��� :"&� ��;"& ��!"&��*���D�;�o���'

;"& ��!"&��(3#+���xD��� :�!�/�0(S�3D:\"&rk �� R�K"&rk19"&%���LDE�/?���T�K�+(3�T ��!���SD�(S�����{x'1*;��T(8DE ��T1Y�$�/7"& :���� x�+EDE�T#T#+ :���K(j�/��DE"zP��1*;�(3 �(31�DE�� :�T�3�*�Aq

��! G)ÆsKºÇT&#456TO^6TNT45-u,PO�L�,�*9È�8;*.&.,=&)&v6�-J4<,=(;8;C�É�45(pKÊO;4»7;8$O^6.?9N�-uD'L�D9O;,=(;4<:98 8J&)(+*=6=NT8;?�8>���^6�&�D'*98

B �� � � ��� � ��� � � � � �������� �� � � �� � � ��� � � ��

�5��$�8 REDE(*�����/��%e"&rGDv;�5�A�8 ��w�;�� :(9#A�!�RDE(*PA"&# � R� "&r�� R��1�@ xR"& .EDE�� R"j�2�0��T�hDv;�5�K(&�T�e�*EDE �"&%���KDE(3 v%0�RDGD�� ��@A�6I(*���+�8(9 x

r�@���&(9�!���3DE(3#�D�"K(jR19�8 �DE(3�w��w��%KD�;�z�!�*1*;�(*�+�/��!\@+����� :#T'�/��%hDE;+������?�*# "9�+�!���jD\"&rb��� 7�8(&��*.(&�R"&13�T(�DE�*�Kth�LDv;hD�;�`����13# �T�+���T�

1*�T :1�@#T(8Dv�T��%~�*EDE �"&%���u# ��?�*#��(3r DE�� ��!���"9�(*@{��jq$yh#LDv;"9@%&;eD�;+�K"&?�(3 :�T�*5(3 ��YDp;���+ :�T��13�w�(9#N�"9@ �1*�K"jr��'ED����!��1>�6vDE :"&%+���~�T�

D�;�5�+ x���!���+"&�(*@AR(3#��"&��2� R��%$�0(9�3D\th"0�V(9��A"*Dv;�8 ��� D��*�"�r.�*EDE �"&%���>P{� "��'$�SDv;�*�� �(3 ��5� R�*����3D�DE;� �"3@+%�;�"9@jD�DE;+��PA"&�&'kg3Dv;�

�!�3�����1S;�'��K(j#�19�*# # 5"�r.(3�&�w�A"07�5D:� ��@A�`(*��u���/�$��"�ED��*"9P# (jvD:�(*���>�{�� E;�(*�A51�;"&��& �"j1S'3D:�*��w��PA"&��*�A?�(&R1�@{#T(9 ��7���"*DE;+�*# �T(3#

(*���)(9"j �DE�T1 ��!"�"*DE;��`@{R13#2�a13�*#T# ��5(&�t`�*#�#z(jCR��?�� :(3#`R�LD:�*u�/� D�;�=P :(9����5�/�019#w@{�&�T��%ODE;�=�!�*���T(3#z;�'&�{"*D�;�(9#�(9�`@{��.D�;�

(*�K'�%+�j(9# �)(S��-D�;+�);�w���A"&1*(9�h��@A*q������!����(*�� �"�EDv�e���"9�(S@{R(3#}th"&�!�����Dv;���6vDE :"&%+��� �'j�3Dv;�*��T�3�*��th�LDv;�w��D�;�*��

��c&DE :(S%0"0�0(&�&(3#\13"0�K�(3 �D��!���3D:z� :"9P(SP#w'm;�(j`��"=�V( ��"& � :"�#2�!(j`(�1*�� �1�@#T(8DE�/��%m;"& ��!"&��*��P�@&D5�/` �(8D�;��� h"0�0#/'~PA� "�#T"&%�21*(3#T#T'

(31�DE�w?��(8D�(5#T"&1*(3#&DE� ��@A��# ��?�*#A�/�V(5��(* �(31� :�w��5"& N�w�SDv :(31* ��w���rE(&�;�� "&�!�E��*��r:"& N :�7?� ��t �R�8l�� �E��q

��cjDv E(*%�"&��(3�&(3#\�3EDE �"9%���=�'��3D�;�*7�/`�/��?"&#T?�*5D�;�������*'��K(8D��T1hDE �(*�RrE"& ��V(�DE� "&���P$'�(9 :"&�K(8DE(&R�*��"&r�(9��& :"&%+���$ztz;�T1*;

P�*13"0�!�bDv;�.� ��T��13�w�(9#{R"9@ �13�5"&rN�*EDE :"0%���\(3r DE�� N�!���+"3�+(3@AR�jq&,."0�h�(9 :�*�`th�LD�;Kt`"&�!���{�$�!���K�K(j�/�SDv(3�w�V(�;�T%�;K1*�T :1�@A#�(�DE�w��%

# ��?�*#5"&rh(91�DE�T?�^� :��1�@ x�"j �Dv�6ED�"�ED��8 �"&��!D�;� �"3@+%�;"9@jD`# �Tr������8�$�E���=�0_ ¥v±&qb���Ed=��_ �w� t`"&�!����:�\tz;0�21*; � >(*?�(9� #T(*P# ��r:"&

(3 �"3�K(8Dv�/�(8DE� "9��A�w����cjDE :(S%�"&��(3�&(3#G7�LD:�**q&]���1*(*@A��.D�;�z# ��?�*# �"jr|13�T :1�@#T(�DE�T��%hD��6vDE"�ED:�� R"9����T�hDv;�5�K(&# �5(3 :��7�T�!� #T(3 �DE"�D�;+� ���

"&ra(3 �"&�K(8DE(&R����W�$�E��� ��_a�:���LDO� �#T�T��*#T'�Dv;�(8Do1*�T :1�@A#�(�DE�T��%�D:�*EDE"�ED��8 �"&����T�¡�!����1*(S��PA��13"0��?�� �D��*���*rEr���19� ���3D:#/'��T�

HA

L author manuscript inserm

-00243083, version 1

¿ ¸

��c&DE :(S%0"0�0(&�&(3#�R�LD:�*\DE"K�+ :"&�9@{19�h�@rErE� 1*�2���SD�#T'�;��T%�;�# "�1*(3#�1*"&��13���3DE �(8DE�T"&��"�r\�6EDv :(3�&� "$#k�@rErE�213� ���3D\rE"& NDE E(*�R(91�DE�w?0(�DE� "&��"�r\�N4

�2P"*DE;α

(S��β, ���h(9 :"9@����C�.��_a��tz;�8 R��(j\�T�Kt`"&�!���hDE;+�Y1*"0��?�� xR� "0��D�"K�6vDE :(9�j�2"�#+th"9@# �zP{�5# �*�I�*rEr:�T13� ���3D�q9f|;��# ��?A�*#A"&r

1*�T :1�@#T(8Dv�T��%�D:�*EDE"�ED��8 �"&��5�w�K�!���!� \(3# R"`W�E�`"& :���� x\"�r��V(S%���LD�@����%� :��(8D��� GD�;�(*��D�;���!��(3�K# ��?�*#A"&r�13�T �1�@#T(8DE�T�&%!�*EDE �(3�&� "&#A�T�

�"�EDv�!���"9�(*@{�(3#�th"&�!�����E�$���El��o�_o�K(*���)�T�«�!���«��W+d���8�$�o�_a�!�E��*�~r�"j > :��?�� ��t �R��l���E��q � �T?���aDv;�(8D`�`@1*;�"jr�Dv;�

1*�T :1�@#T(8Dv�T��% �6EDv :(3�&� "$#~� P{"9@+���D�"���7c�;+"j ��K"&��3�2PA�w����T��%¡%#T"9P�@A# �T����LDO� O@+�# �w��*#T'�DE"¡;�(*?+��(��K( ��"& O�T�K�(91�Da"$�

DE E(*�R(91�DE�w?�(8DE� "0��"�r~Dp;���N4Y�^1*"&�K�(3 ��*��t��LDv;��*EDE �"&%���¡� :"&�9@13�*�¡# "&1*(3#2#T'�(j«(�1*"9�$7� �9@{����19��"�ro(3 :"0�V(�DE� R(8DE�T"&� "&r

1*�T :1�@#T(8Dv�T��%)D:�*EDE"�ED��8 �"&��&q�f|;&@{���D�;��m@+��T�3D��8 � E@��jDv�8���@rEr���19� ����1*'�"&r�13�T :1�@+#�(�DE�T��%)D��6EDv"0vD:�� :"&�+� �/���!��� Dv;� :"9@%$;"9@jD�#T��rR�

�@����+"j �D:>D�;��aR�T%���� rE� 1*(S�3D!# "&1*(9#5� :"$�3@+1�D:�T"&��"&re�*EDE �(3�&� "&#zP�' DE�*EDE"�ED��8 �"&��m(9 :"&�K(8DE�2�*(8DE�T"&��5(S�0�«13"9@{#2�O� :"9P(SP#w'-(3rErE"& R�

"&��%"&�T�$%~� �"*D:��1�D:�2"&��(S%�(3�w�ED��*EDE �"&%���m���*r:�T13�2���01S'� ��*#T(8D��*�m�j� 7�8(&��**q�y� :"&�K(8D��T�*(8DE� "0��� z� �"3P+(*P#w'a�T�`�{"& �DE(*�3D5�w�^D��� E�!K"&r

� :"*DE��1�D��T��%VDv;�5PA"&��*z"jr\�!���u(9%�(3�T�EDZ�!�T��� :(3#�# "�� �R�8l�� �x��(*���>�!�T%�;3D.(3# R"�19"&�3DE :�wP�@jD���D�"hD�;+�`�V(&�T�3D����0(S��13�K"&r.13"&%$��LDE�T?�

r�@���1�D:�2"&�V(S����� ���?���3D:�2"&�V"&r�y����T�K�!���Gq

B��?+�8 �(3#5rE(31�DE"& R��`@{ED`PA��D�;&@{KDE(S����-�T�3D�" (91*13"9@+�SD}t�;���)19"&��� �$�8 ��T��%aDE;+�u�+;�'R� "�#2"&%�'-"&r!�*EDE �"&%���-#2��?�*# *q\�E�

%����� :(9#/�|"&?�(3 ��T(*�aEDE�� :"�� ��`(9 :�!19"9�13���3DE �(8DE����7��?�� :(9#/��r�"�# �m�w�CP :(9���m R�8#T(�DE�T?�`D:"��#T(j��V(&�N(S���eD�;+�hD�@ v�"&?�� � �(8DE�>"jr�P :(9���

R� �9@{�*EDE �(8DE�T"&��"&rNPA#T"�"���2P"& ����7��c~ED��8 �"�� ���� .;+�T%�;!13"0�K�{(9 :���Kth�LDv;e"*DE;+�8 .ED��8 �"�� ����@+1*;!(jI13"& �Dv��19"�ED:�� :"$� �� �TW+���q���@+��DE"

D�;�K���TrEr��8 R���19�K�T�u���T��RD:�21!�&� rEr�@{R�2"&�u :(8Dv�65(91* :"��.Dp;�`P# "�"$�!P+ :(3�w��P(9 : :�T�� �r�"j 5�*EDE �"3%+���$��� �"&%�*ED��8 �"&��K(*�+�VD��*ED:"�EDv�8 R"9��3�

D�;�`� R�*�����19�!"�r5# "&1*(3#2���9�*��P �(3�T�C��7@ :"�ED��8 �"�� ��z(*��u(9 :"&�K(8Dv(jR�*��(*�+�!DE;+�`�{"��7�wP# �>?�(3 :�T(�DE�T"&���T��� :"&%+�3ED:�� :"0��K R�*13�7�jDE"&

���T�!�� R���*(�DE� "&��0P#T"�"��5DE�*ED:\(*���K��� E@+��#2��?�*#A��?�(3#w@(8Dv� "&�K(3 :�I%����� :(9#�#/'h�"*D�?�� �'h;+�*#��+r�@{#+"& N�T��r:"& ��V(�DE�T?� � l�X��q

B � �� ����� � ���� � � � ������� ������ ����� � �� ����� ���

���LDv;0�/�-D�;� m19"&�3D:�7cjDu�LD��K�T%�;3D�PA�)�7c��{��1�D��*�)D�;�(8Du ��67��(3 :1�;�(9�T�!�w��%-D�"��6EDv(*P# � �;�(�1*"& : ��*#�(�DE�T"&��PA�xDvth�*����7�8 �� 1

�����"&%+���"9@{z;"& ��!"3��(&#N# ��?+�*#/z(9���~��� 7�8(&��}th�LD�;~(>%����$�3 �����1*� rE� 1}�(8D Dv�8 v�~th"9@A#T��P{�>�T�19"3�+13#w@{R�T?+�K(*��C13"9�3DE :"0?�3 RR�T(3#Eq

��;�� R�8(&KR"&�!�evD�@{�$� �6`19"&���9@{1�D��*�~�/�a�*# ���� :#T'mth"0�!���m;(*?���;"&tz�~�"�7�LDE�T?�> x�*#T(�DE�T"&�R;�w�{zPA�RD�th�*���a;��T%$;a�����"&%���+"3@A

R�� E@+� #2��?�*#�m"$r~�*EDE �"3%+���$o��(9��)D:�*EDE"�ED��� :"&��*�>DE"��"0�!�O?�� EP(9#K�!���!"& �'�r�@��1�D�� "&�m(S�0� ���%�(8DE�/?�O x��#T(8DE�2"&�R;�/�{uDE"

?� �@"���(�DE�T(3#�r�@�1�Dv� "&���A"*Dv;�� �ED�@���2�6�;�(S?�`�"*D\r:"9@�+�!(*�$'e R�8#T(�DE� "&��;�w�{�t��LDE;u13"9%��+� D��w?�z�{�� :r�"j ��K(*��13�K��f\(*P#T�`W���q�_o"j R�

:��13���3D�#T'�&Hh"0%�8 v?"& xED��RD�(3#Eq9 :�7�"& �DE�*�5Dv;0(�D�;��T%�;K# ��?�*#�\"�rADE"*DE(9#A�6vDE :(9�j�2"j#+;�(9�h(5�+"0�� D��T?�� :�*#T(8Dv� "&��;�w�!t`� Dp;K?�8 vP(3#+�!���!"& �'

�T��th"&�!����+P$@jD|�"*D.�T���!����Atz;�8 R��(j\DE"*DE(9#D��6EDv"0vD:�� :"&�+��;�(3�>(`���%�(8DE�/?�h ��*#T(8DE� "0�VDE">?�� EP(9#G ��*1*(3#T#��3��{��13�T(9# #T'e�/�et`"&�!���kq

���VDv;�`"*DE;�� \;�(*������"&�!�K"*D�;+�8 I?�8 vP(3#��2�(3�T ��*�!(j7R"�1*�T(8D��3��+%� �(3�&�*�>�0(9�!�T�$%0�\(*�+�!?+�/x@"���(8Dv��(9#DE(&��5�2�(3�T R�*�!(&�R"&13�T(8Dv�6��

:��13"&%$�0�LD�� "&���Y�;"&t`�*�u�"� x��#T(8DE�2"&�R;��w�{zth�LDv;~;�"& ��!"&��!#2�*?�*# *q+HK����13�*���+"6D�(3#T#\13"9%���LD��w?�!r�@+��1�D:� "0�$z13"9@#2��P{�>�T�K� �"&?�*�

th�LD�;K;�T%&;�� N# ��?+�*#�\"&r�7�7ceEDE�� x"&� ��\(S��Vx@1�;!�8r�r:��1�D:.7�*���e�*�5DE"�PA���!"����Tr:�2�*��P+'}���cGi3Dp;�Y7��cA�E����7� D��w?�bD��*ED:.�;"0th�T��%�D�;�

HA

L author manuscript inserm

-00243083, version 1

�
1*# ��(3 :�*ED|�8rEr��*1�D:|th�LD�;`�{"��R�wPA# ���/�SD��� :(31�Dv� "9�!"jr�(S%��t��LDv;V#2��?{�*# \"�rNR�7cK;"& ��!"&��* �R�8l&W ��q

FG"�����P+# �h(&�R"&13�T(�DE� "&�5"&r.��� R��1`;+"j ��!"&��(9#k#2��?�*# �th�LDE;u���S�!���jDE�T(K;�(S?�h(9# �"}P{�*���~�/�j?+�3EDE�T%�(8Dv�*�{q�BA���0(S��(3 :"0�j%]¤@§u³ ¬ �

:�7�"& �D��*���GD�;�(�D5# "&th�� h�*EDE �(3�&� "&#.# ��?�*# }th�� R�!13"& � :�*#T(8DE�*�Ct`� Dp;m�"�"& �13"0%���LDE�T?�*��P{��;�(*?+� "& :(3# ����7@ :"9�{�'�1*;�T(8Dv :�T1u�'��!�&DE"&�!

(*���Cr�@��1�D�� "&��(3#.EDE(�D�@{z�����8��dC19"&�K�K@+�0�LDv'�2P(j7�*�~"$# ���� 5�!���a(*��Ct`"&�!���a"&r5t�;"&��l&Wm;�(9�m�����!���jDE�T(u(S����$�C��� ���"*D

�R�8l����q�fN;�7'a���*rE�T�+�*�~(!Dp;0 ��6�;"�#2�~# ��?+�*#."jrz�����"&%���+"3@A`�6EDv :(3�&� "$#b�T�uD�;���*# �$�8 R#w'�r�"& �D�;�> :� ��a"&r�����?�*#2"3�A�w��%a�����!���jDv��(

P�*�T��%!#2�3�ND�;�(S�a�8d`�+%���!#G� �md�d`�+_a�N�T�>�!���e(S��!# �*�|D�;(*�a�I��%���!#��w�!th"&�!��� �R�8l����q&f|;�� NDv;0 ��6�;"�#2�K?�(3 ����*�7"&�!��t�;�(�D

rE :"&��Dv;�(8DN ����+"j �D:�*�`P+'!_a(S��#T'M¤@§^³ ¬ �+t�;"Kr�"9@���Dp;0(�DGD�;+�h ��/x�!r:"& Ny����T�K�A"�EDE�!���+"&�(*@AR(3#+th"0�!���et�(&.�T��1* R�8(&R�*�!U+��rE"�# �

rE"& N�6vDE :(9�j�2"�##2��?�*# \# �67�D�;�(3�KW�z��%���V#�R�8l&U��:�&th�LD�;K�+"VR�/%���Tr:�T1*(*�3D�(&�R"&1*�T(8DE� "0�Kt��LDv;!�6vDE :"9��5��� E@+��# ��?+�*#/Sq

���e(` :��13���3D\4Y,IfO1*(* : :�T�*�>"3@&DNt`� Dv;a��W�};�'ED��� x��1�D�"&�!�T�3�*�>�"�EDv�!���"9�(*@{�(3#At`"&�!����th�LDE;>y �`�+�"K(&�R"�1*�T(8Dv� "&��t�(j

rE"9@��`PA�RDEth�*���u�*EDE �(3�&� "�#�"j \�*EDE :"0���# ��?�*# I(3�+�K��7@ :"9�{�'1�;"$# "&%�� 1*(3#�D��*EDbR19"& :�*�"0�el!�$��r�r:�� :���3DN(&�7�6���!���3D:.(�D�P(&��*# �T��

1*"&�K�(9 :�*�KDE"�W~"& >��Wu�!"0�SDp;$zrE"�# #2"&th�2@�� �R�8l�d ��q � �*�� x#T�T�$%$�¤@§s³ ¬ ��(3# R"�19"3@A# ����"*D�rE�T���(*��'u(&�R"�1*�T(8Dv� "&��P{�RDvth�*���~;+�T%&;�8

# ��?�*# �"&r.�����"&%���+"3@ANDE"*DE(9#G"& NPA�T"&(3?�(9� #T(*P# �z�6EDv :(3�&� "$#A(*��K R�*�9@13�*�K �� R��"�rb�$���!���jD:�T(`�T�ed �3U>th"0�!���^"& \UX��}�!��� �R�8l����q

<K"e7�w%���Tr:�T1*(9�3D\���Tr:r:�� :���+13�*5�T�u�6vDE :(9�j�2"j#�# ��?+�*#/Yth�8 R��r�"9@����w�e(Kr�@+ �D�;�� ���V(9# #kEDp@�&'u"&rbWN��y ��(S��a��W^;�8(9#LDE;�'�th"0�!�*�

�R�8l�l��q{Hh"&%�� E?"& RED�¤@§P³ ¬ �|rE"3@$��u�+"~�&� rEr��8 R����13�>�T�~r:���!(9# ��D��6ED�"�ED��8 �"&��!#2��?�*# 5PA�xDvth�*���m1*(j7�6z"�r�y���(S��u19"&�3DE :"�# *q�].'

1*"&�3DE :(&ED:���!���mt`� Dv;my��¡;�(j�mR�T%$��Tr:�T1*(*�3D�#T'�#2"&th�� �# ��?�*# K"&r.D��6EDv"0vD:�� :"&�+�6�|t�;+��1S;�19"9@{# �C�T��$��1*(�D:�`D�;�(8D5# "0t D��6vDE"�ED:�� R"9�{�

�V(9'`P{��(�1*"����!"& EP+� �hr��8(�D�@ ���"&r�y����T�K�!�����"& GDp;0(�D�#T"&t Dv�6ED�"�ED��8 �"&���#2��?�*# \13"9@{#2�K��c(91*�8 vP(8Dv�bD�;�5��� 7�8(&R� �R��l � ��q

[G�w��(3#2#T'�$HV"&%+�8 R�?"& xED.¤@§;³ ¬ �+�"��T�3D��*�!"9@jDGDv;�(8D�D�;�h7���R�LD:�T?+� Dp'^"&rGDv;��(&�R(S'!13"9@{#T�����RD:�� ��!�T���Dp;�� R���+"j �D:�*�}?�(3#w@{�`"&r

D�;�>�6EDv :(3�&� "&#\# ��?�*# �R�8l�X��q+f|;��'~1*(3 E ��T�*�~"9@jD�(>�!�xDE(&��(*��(3#w'7�/�DE"u(&�R�*��t�;�RDE;�� .D�;�!R���7�LDE�T?�LDv'~"&rbDv;�K(j��(*'�"&rI�(jED

ED�@�&� �*z;�(3�u(9rEr:��1�D:�*�>D�;�K R���A"& �DE�*��# ��?�*#\"jr\DE"*DE(3#\�*EDE :(9�&� "�# ��(*���u(9# R"u�!��(jx@ :�*�!Dv"6Dv(3#\�6EDv :(3�&� "$#N�T�����^th"&�!���Cth�LDv;~y��

(*���-�&W�13"0�SDv :"�# *q.f|t�")(j7R(*'^th�8 R�C@{7�*�aD�")(j7R�67!Dv;�a�$��r�r:�� :���19�CP{�RDvth�*��� 7���R�LD:�/?�a�� :(9��� "&�T�!�`@+�"&(j�R(S'-t`� Dp;-(

����13�Tr:�T1` :(SP�P�LDN(S�SDv��P+"��&'�A�`�_o�N(*���K R�*#T(8DE�w?�*#/'e�T�7���$7�LDE�T?�`���T�!�`@�+"j(&�R(S'$�A�$l`�_o�N(j��(S'$Sq3f|;�5�!�RDE(j��(S��(3#T'7�/�"�r���T��

ED�@�&� �*z�T����T1*(8D��*�KDE;�(�D.�T�����7�LDE�T?�K(&�R(*'�%�(9?�`;�/%�;�� Y#2��?�*# �"&rbD�"*DE(3#|�6EDv :(3�&� "$#�t�;���~(>#T(3 E%+�K�&@�`PA�8 5"&rYR(9�`�# �&5rE(3#T#

P�*# "&t�D�;�!#2��?�*#N"�r��T�����7��?+� Dv'~"�r\D�;�}�!�xDv;"��AqAf|;��/z�K�T%�;3D���c$�{#T(3�/����(3 �#��2�8 5 :�7�"& �D��"&r�#2"&t�# ��?�*#��"&rbDv"6Dv(3#\�6EDv :(3�&� "&#\�T�

y��h�AR�T��13�.D�"*DE(3#��6EDv :(3�&�T"�#�# ��?�*# ��2@{��T��%hD�;��7�����LD���?+�Y(&�R(S'0�|�T�!13"&�3DE �"&#/Ith�� R��"9��.DE;+�� ��!"&rGD�;+"07�5 R���"& �D:�*�K�T�hDp;���3(9 :#T�T�8

ED�@�&� �**q ��7�T��%hDv;�h7���R�LD:�/?�5(j�R(S'hDE;+��'er:"9@+���hDv;0(�D�th"0�e����th�LD�;�y���;�(9�e7��%$��Tr:�T1*(9�SDv#T'!;�/%�;�� .# ��?�*# 5��W��� �8�}�_a�|"�r

DE"*DE(3#\�*EDE :(9�&��"$#GDE;�(S�~13"&�3DE �"�# h��W|� � �8�^�_a��q ������$%eDE;+�!�T�7���$�� D��T?�K(&�R(S'$��D�;��8 R�Kt�(&5�"CR�T%���Tr���1*(S�3D5���TrEr:�� x����19�!�T�eDp;{�

# ��?�*# ."&rADE"*DE(9#A�6EDv :(3�&� "&#Eq9fN;�5����R�LD��T?��LDE'!"&rAD�;��(j�R(S'V1*"9@A# �5D�;&@{|;�(3?+�Y�$�xD��8 ��!�T�+�*�YD�;+�.� R��?�� "9@{7#T'V ����A"& �DE�*�`?�(9#�@A�5"�rAD�;�

�6vDE :(9�j�2"�#G# ��?+�*#/SqABjDp@�&� �3I@{R�T��%�(!R�7�$7�LD:�w?�`(j7R(*'��j">�"*D\ :�7�"& �D.R�/%���� rE� 1*(*�3DE#/'^#2"&th�� .# ��?�*# 5"&rkDv"6Dv(3#��6vDE :(9�j�2"�#G�T��th"0�!�*�

th�LD�;ay��h�|tz;�T1*;m(3 E%&@A�6`(S%�(3�T�ED.Dv;�>;�'&�{"*Dv;�*�� 5Dv;0(�D5# "&t�# ��?+�*#/>"&r.D:"*DE(9#.�6vDE :(9�j�2"�#b(9 :�>(u :� ���rE(91�D:"& �r�"j �y �>q�yID.Dv;�

HA

L author manuscript inserm

-00243083, version 1

à �

� :�*7���SDzDE�T�!�*�bDp;�~ R��(jR"0�$^r:"& !�*EDE �(3�&� "�#5�T��1* R�8(&R�m�T�)y��� :���K(3�T�O@+��13# ��(3 R��"9��m�7c��A#T(*��(8DE�2"&�OP{���T��%)�N4 �"�#T'��!"& v��;�T1

?�(3 :�T(SP�T# �LD�'!�w�Ky ��1*(&R�**q

f|;0�`(j7R"�1*�T(8DE�2"&��P{�RDEt`�*����ED��8 �"��T��;"& ��!"&��K# ��?�*#|(*���13"0%���LDE�T?�Kr�@$�1�DE� "&�+�T��%!D�;&@{5 R���K(3�T�z1*"&�3DE :"&?+�8 RR�T(3#�(9���(8D

D�;��� R�67���3D�DE�T�!�o�LD!� uEDv� # #�@��19�8 �DE(3�T�)(&KDE"Ot�;+��1S;-ED:�� R"�� �)7�8 v@��# ��?+�*#�� KDE;+�uPA�xD2D:�� K� R����� 1�DE"& ��E�*EDE :(9�&� "�# �5�*EDE :"9��*�

DE�*ED:"�EDv�8 R"&�� �a�:�$@$����� Nt�;+��1S;!r:"& ����TD:"*DE(9#A"j |�"&��2� R"*D��8�T�A�2P"9@��K(S��`P� "&(S?0(9� #T(*P#2�*�:�$t�;�RDE;�� �D�;� .19"3@+# �`P{����A��13�Tr:� 1zrE"j

"&�#w'e7"&�!��13"0%���LDE�T?�zr�@��1�DE� "0�$I(*���Dv�T�!�5�A"��w�SD�.(*�+�!��?�S�hD�;�`�j�T R��1�D:� "9��"jr�DE;�5(&�R"&13�T(8Dv� "&�e�E�/�01* R��(jR�z"j \����1* R�8(&����8q9fN;+�

#T�T���!t��LDv;}7�8 v@� %"9�0(&��"*DE �"9��T�.�3¤�� Â��+#w@jD:���T��T�9�T��%K;"& ��!"&��*���M�H`�:��(S��Kr:"&# # �T19# �YED��T�`@{#T(�DE�T��%K;"& ��!"&��*.��[NB$Hh��t�;+��1S;V(9 :�

R�����LDE�/?�bD�"K1�;�(3�$%�6I�T�!�*EDE :"0%���V(S��5DE;�I� :�/�V(9 E'! :��%&@A#T(8DE"& N"&rN�*EDE �"&%���K� �"��9@1�DE� "&���N(9# R"h R���K(&�T��DE"�PA�513#T(3 ��TrE� �*� �R� �j���

� �G� ��q���;�RD�;�� N(h��8 �� 1.D�;� x�*�;"$# �h19"9@{# �zPA�����*r��T��*�`r:"& N(*�&'!"&rAD�;�37�YED��� :"��T����$t�;�RDv;�8 �D�;��/�Dv;� :�*R;+"�# �`�/I�&�/vD:�T��1�D�r�"j ��!�*�

(*����th"0�!����"& .tz;�xDv;�� �"9�jD��T�K(3#N# ��?+�*#/z"&r�ED��8 �"�� ��5(3 ����+�*�*���*�!DE"��K(&�T�3DE(3�w��P �(3�T�ur�@��1�Dv� "&�uth�LD�;��"KDE;�� :(S��7@jDE� 1`?�(3#w@G�

rE"& .�N4�f)"9�19��y���� I� R�*����3D\(3 ��h�"0�!�K"jr�Dv;���9@A�6vD:� "0�$It�;+��1S;e R���K(j�/�!@+�0(S�Rth�� R�*�Aq����3D:�� R�6vDE�T��%#/'$�$D�;�`(*P{����019�K"&rb(9�

(j��"j1*�T(�DE� "&�Kth�LD�;K�+"0vDE�!���"0�(*@{�(3#+�6EDv :"&%���!#2��?�*# .;�(&\(3# R"zP{�*���! ����A"& �DE�*�}t��LDv;!"*DE;�� ��(�D�;�"�# "&%+� �6.x@1*;K(jI"0vD:�*"9�"& :"�7�

(*���o?�� �D���P �(3#�rE :(31�Dp@ :�*��.rE"& `t�;+��1S;�Dv;��� :"*D��81�D��w?�m�*rEr:�*1�D`"&r!�*EDE �"&%���)� >���?�� �D�;+�*# �3�>th�*#2#Y�$"j1�@+�!���jD��*� �R� �9W �8q|[G"&

P :��(jvDb1*(S��13�� x��Dp;0�`�&(8DE(K(S?�(3�T#T(*P# �zrE :"&�¡� :"���A��1�D:�w?�KED�@�$� �6�"jr.�*EDE �(3�&� "�#�# ��?�*#�(*�!"0��%!� R���!���"9�(S@{R(9#Gt�"&�!���u(9 :��(9#/7"

�T��13"&��19#�@AR�T?�«t�;�� R�8(&mrE"& u�A"�EDv�!���"9�(*@{�(3#`th"&�!����(��"���LDE�/?�O(j�R"$1*��(�DE� "&��t�(jax;"&t���P{�RDEt`�*������� E@+� �*EDE �(3�&�T"�#

1*"&�19���SDv :(8Dv��"9�K(S��C :� R�K�E7�*��r:"& � R��?�� ��t �R� �j�����q��z�� R��18D5���RD��8 ��!�T��(8Dv� "&�a"&rh7�8 v@���*EDE :"0%���a# ��?�*# ��\�*��A�*13�T(3#T#T'O�T�^Dv;�

� :���!���+"3�+(*@{7�K�A�8 �� "����|�K(*'uD�;&@{`�"*D5 ���� ��67���3D.DE;+�KPA�6EDz�!��(*�K"&r��$�xD��81�D��T��%m :�*#T(�DE�T?���*EDE :"0%���a����r:� 1*� ���+1*'�N(&K��8 v@�

# ��?�*# .r�#w@1�D�@(�DE�5(*���D�;+��# ��?�*#�"jr|(3�&'e7�T��%�# ���3vDE :"9%���>�V(9'!�+"6D|(3#wt�(*'. R��r:# ��1�DGDp;��DE"*DE(9#G�w�3D:��%� :(�DE�*�!���+�0�v"& E%�(9�e��rEr:�31�D�."&r

�K@#LD:�w�#2��19�T :1�@#T(8Dv�T��% 13"&�K�"9@+���«�{"��7�*�R�T��%��*EDE �"&%����T1�� �"3�A�� �DE� �* �R� �3U ��q>_a"& :��1*# �T�+��1*(9# #T'¡@{7�8r�@A#C�!�8(&�@ ��6 "�r

�����"&%+���"9@{.�*EDE �"&%����T1��*rEr��*1�D:\(8DAD�;��5# ��?�*#A"&rN��A�*1*� rE� 1.DE��7�@�*.���"*DE(SP#w'hP �(3�T�����`@{ED�PA�Y7"9@%&;3D:�$r:"& N�T�EDv(*��13�I@{��w��%!F���f

R1*(*�\�w�K13"&�KP�/�0(�DE� "&�`th�LDv;hP�2"&�V(9 E��� xSq

F � �� � ��� ��� ��� � � � ��� �� ��� � � ���� ��� ��� ��� � � � � ��� � ��������� � � � ����� ���������

y5�(3 �D\rE :"9��1S'�13# �T1`?�(3 ���(�DE�T"&�5�w�~��� E@+��;�"& ��!"&��(3#�# ��?�*# 5�9@ ��T��%� :�7� :"��9@A1�DE�T?�`# �Tr:�*��?�(3 :�T"9@{�13#2�T��� 1*(3#��K(3 E�+�8 R�(9 :�

1*(*��&� �&(�D:���/��&� 1*(8DE"& R�"&r\# �Tr:�*# "0��%u�����"&1* :�T�+��r:#w@1�D�@+(8DE�T"&�*q+�N(* �#��2�8 .(S%��(8D|�!����(3 �1�;�h� ������'��(3 RR�|tY;+��1S;erE(9?�"& x�(`;��T%�;��

D�;�(*�!(S?�8 �(*%�z�3EDE :(9�&� "&#G��� E@+��# ��?�*#�r:"& `�8��DE"!�$�`'��(3 R.(3r Dv�8 \�!����(3 �1�;�*�+�&@{#2#��w�(9 :�LD�'!(9���!#T(8D��5r:�T xvD�� ���%���(S�1�'^��(9r DE�* Z�$�&�:�

(*����#T(8DE� �!���"9�(*@{7� ��(9r D:�� ~d�d0�e(9 :�o(*�!"&��%)Dv;�m�+;�'��2"�# "9%� 1*(9#hrE(91�DE"& xC(j7R"&13�T(8DE�*��t`� Dp;�(*���T��1* R�8(&R�*���7c��{"��@A :�CDE"

�6vDE :"&%+���$SqN,."&��?+�8 R���#T'a(C#�(�D:�� `(*%��(8Dz�!����(3 �1�;�*�|� :��%��+(*��1*'a(S��a#T"&��%+�8 5DE�T�!�~7�T��13���!���"9�(S@{��� ��6�@A#LD��T�O���*1* :��(j7�*�

��c$�{"��@ ���D:"C�*EDE :"9%���A*q���P�*7� Dp'��9@ ��T��%eD�;+�K13# �T�K(31�D��� :� 1>�/z(3# R"�(!�+��'~rE(31�DE"& 5(j7R"&1*��(�D:�*�^th�LDE;~(S�~�T��1* R�8(&R�!�/���*EDE �"&%���

HA

L author manuscript inserm

-00243083, version 1

Ã�¿

��c$�{"��@ ��jqZy�r D��� hD�;�=�!���"&�(S@{R�*���!�*����1S;�'��K(3#�19�*# # u"&rK(&�&�w�{"�7�eD�� ��@A�uPA�819"&�!�uDv;�C�V(&�T�-7"9@ :19�m"jr>�6vDE :"&%+���)?�T(

DE�*ED:"�EDv�8 R"&���(3 �"&�V(�DE�T�*(8DE�2"&�Gq3f|;�� x��r:"& R�*���T��Dv;���"�ED:�� R���+ :"��9@1�D��T?��'��(3 R��3Dp;�5��cjD����3DN"&rNr����V(&# ���*EDE �"&%����T�*(�DE� "&�!� \�!(9�w�#T'

���RD:�� ��!�T��*�>P'u(&�&�w�{"�7� Dp'�q+f|;� �� z"&r.13# �T�+��1*(9#N�T�`�{"& �DE(*��13�K19"&�R� ���� R�w��%eD�;�(8DI13"& E��@+# ���3D.th"0�!���~(3 ��h R�*#T(8DE�w?�*#/'e�+ x"*DE�*1�D��*�

(*%�(3�w�ED�y�� �R� �jd �k(S��`"0vD:�*"9�A"j �"��� �R� �j� �GP$@jD��V"& R��(�DG �� ��V"&rN�*EDE �"&%���K�����A��������3D�P :��(jvD�1*(*��1*�8 �R� �jl��q

FG ���%$�0(S�1�' �/«(j7R"&1*��(�D:�*� th�LDE;�x�{��13�Tr:�T1�?�(3 ���(�DE�T"&�*q�B��� E@+� �*EDE �"&%���-�v�6vDE :"&�+�6���6vDE :(9�j�T"�#�(*��¡�6vDE :�T"�#T�a(S�{�

� :"9%�*ED��8 �"&��O# ��?�*# C(9 :�a�/�1* :��(j7�*�)?+�8 �' �9@�T1*�#/'��3@+ :�T��%�� ���%���(*�1�'�zt�;�� # �OR�!"0��T��%��9@ ��T�&%-� R��%���(S�01S'�#2"&th�3 >D�;��

�V(�D:�� E��(9#u�6vDE :� "$#e#2��?�*# oP'�W�$� "& m�!"& R�OD�;� :"9@%$;"9@jDm�+ :�7%���(*�1S'�qzy�r D��8 =�(3 �D�@� :�LDE�T"&���R�8 v@� �*EDE �"&%����#2��?�*#�O(* ��

�& :(*�K(8Dv��1*(9# #T')���*1* ��8(&��*�=P�@jD`(8DK�@rErE�T19� ���3DK# ��?�*# `D:"o13"&�&DE�w�j@A��DE")EDE�T�`@{#T(�D:���+ :"�#T(31�Dv�T��C# �wP{�� :(�DE�T"&� r�"j KW«�j(S'*q �5@+ :�w�%

#T(31�DE(�DE�T"&����*EDE �(3�&� "&#A# ��?�*# \(3 ���(&N#T"&t�(j|(8D��"�EDp�!���"9�(*@{��Y�E7�*��r:"& N ���?+� ��t �R� � � �:��q

4���%�(9 :�&�T��%u�7c{"&%+���"9@{5�����"&1* ��T��`�*rEr:�*1�DE"& x7�+@{R�z"�r �z,��(*���K�A"�EDv�!���"9�(*@{�(3#G�|4�f)�2t�;"�7�h�&"�R(9%��� �%���+�8 �(3# #T'

# "&th�� �D�;�(*� ��,�R�:�&D�;�*�T �DE�T�!�5(*��>�9@ :(�DE�T"3��"&r�@{7�Y(9 :���7cA"&%���"9@{IrE(31�DE"& xI(3# R"K19"&�3DE :�wP�@jDv�T��%hDE"}�!"����TrE'��6EDv :"&%����# ��?�*# ��

t�;"�7�Y��rEr:�*1�D�\13"9@# �zP{��r�@ �Dp;�8 ��!"��9@{#T(8Dv�*�h�T�K1*(j7��"&r�13"0�KP�T��(8DE�2"&�ht`� Dv;`� :"9%�3EDv�T�*q3]\'K13"0�SDv :(jvDp�0(��&�81* R��(jR�*�K�7c�+"0x@ R�

DE"m�*EDE :"0%���`13"9@# �C R�6�@+# D5rE �"&��?�(3 ��T"3@AK��?���3D:��|�T��13#w@A�&�T��%m1*(jEDE �(�DE�T"&�a��(3r D��8 hx@ E%��� E'�N1S;���!"3D�;+�8 �(*��'a"& � �(3�&�T(8DE�T"&���:�|"�

��c$�{"��@ ���DE"}?0(9 :�T"9@{�13"&�`�A"3@+���\�+"07��*�7�T��%!(*�3D�� �*EDE :"9%�S��T1�(31�Dv�T?�LDE'�A�@+1�;!(jNDv(*�!"9c{�Tr����^��"& ."*D�;�� �B+�N4�_o�:�$� :"9%�3EDv�����

(*�3DE�T(*�+�j �"&%�����+��t�;�� 1S;V19"9@{#T�zP{��@{7�*�hr�"& GDE :��(8Dp�!���SD|"&r�;"& ��!"&��(3#A���7�{���+�����3D�1*(3��19�8 RR�:� � �04IH�(*%"0�0� ED�.�2@{��*�K�/�hP���+�T%�

1�;� :"&��T1`%�'$��*13"&# "&%+��1*(9#���� �"& :�$�8 R�"& .rE"& ND�;��DE R�8(�DE�!���3D\"�r�EDE�� :�2#��LDv'��."j .�$� �xDv;�'�# ED���#wPA�3EDE �"j# ���.B~�pt�;�T1*;�;�(jIP�*���>@{��*���T�

D�;�I�(jED+DE"`(*?�"�� �`�K� �1*(9 E :�T(*%+���9@ :�/��%h�+ :��%���(*��1S'0��q

f|;0�K7�8(9 :1�;ur:"& �1*"0�$��/vD:���3D.(&�R"&13�T(8Dv��"0�$YP{�RDEt`�*���~�����"&%+���"9@{��*EDE �"9%���~# ��?�*# 5(S���13"&%$�0�LD��T?�`r�@��1�D�� "9�u;�(j�P+�*�*�

�T��13"&��19#�@AR�T?�&q+y��~�/�SD��� :�*ED:�/�j%u(&#LD:�� E��(�DE�w?�!� �P"0��`�!�T��� :(&#N�����R�LDv'~�E]._��z�:��t5;� 1�;~� 5(}�"*D:���3D���(9#N�@ : �"9%0(�DE�`�K(3 E�+�3 �rE"&

�����"&%+���"9@{��*EDE �"&%���Gq+]�"&�+�K13"&�3DE(9�T�5�N4Y��(S�0��]._���� ��"���LDE�T?+�*#T'u13"& : ��*#�(�DE�*�>P{"*Dv;uth�LD�;m�����"9%���"0@{5(*�+�u��cA"&%���+"3@A

�6vDE :"&%+���$�(9����13"9@{#T�KD�;&@{IPA�h19"&�R� ���� R�*�!(K�K(3 v��� .r:"& .# � r��8# "0��%u�6EDv :"&%���C��c��A"��@ ��jq$]._���� �(3# 7"!(*�u(&�R"&13�T(8Dv�*�!r:(91�DE"&

�T�m?�(3 ���"9@{V;"& ��!"&��*�E���7�{���+�j(9�3D��(�D�;"&# "&%�2�6*q�[G"& `��c+(3�K�+# �6�|;��T%$;a]._�� ;�(&zP{�*���aR;+"&t��uD:"�P{��(��V(9 E��� �rE"& � �����a"&r

P :��(jvDh1*(S��1*�8 �R� �&X����8X&W �:�Zt�;�� R�8(&Kt`"&�!���Oth�LDE;O;��T%�;�� KP+"3�+�C�V(&���\;�(S?�u(m����1* R�8(&����a ��/��)"&rh19"�#T"&� 1*(9��13�� ���8X$��:�

� :"9P(SP#w'� ��*rE# �*1�DE�T�$%m%0 R��(8DE�� �1�@+�h@A#T(8DE�w?���3EDv :"9%���a��c��"��@ :�&q�]._��¡t�(j`(9#/�"~ ����A"& �DE�*��D:"�PA�!(��K(3 v��8 z"jr51�@+�K@{#2(8DE�w?�

�6vDE :"&%+���~��c$�{"��@ ���(j7R"�1*�T(8D��*�>th�LD�;u13"&%����LD��T?�`r�@��1�DE� "0�^�/�e�+"&��E�����!���jD��*�u"&# ���� .t`"&�!���Gq��`(3rEr:�Q¤@§u³ ¬ ��;0(S?�KR;"0t��VDv;�(8D

th"&�!���mth�LDv;�"�ED��*"9�{"& �"07� ���t�;�RDE;�� z�!�8(&�@ :�*��P�'CP(j��*# �T��>]._��h�| :�*�9@1�DE�2"&�`�T��]._ �h�|"j �?�8 �D:�7P �(3#\rE E(31�D�@ ��67��;�(*?�

�"�"& :�� .13"0%���LDE�T?�`r�@+�01�D�� "&��(*��^%0 ��8(�D:�� . :� ��u"�r.1*"0%���LDE�T?�K�$�xD��8 R� "& �(8DE�T"&� �R�8X&U ��q+]._�� t�(&�(3# �"�R;+"&t��VD�"KPA�`(j�R"&19��(�DE�*�

th�LD�;m?�� EP(9#\�!���!"& :'m�T�K�(9�T :�!���3D��v���*#T(*'�*�C :�*1*(9#�#2�Y(S�!"&��%mU�T���&Um��# ���� :#T'a�@�P����*1�D:`�T�uD�;�>fN;�T ��e<K(�DE�T"&��(3#|HV��(3#LDv;�(S��

<`@jDE ��LDE�T"&�V��c(9�!�T��(8DE�T"&�uB$@ E?�7'!�R�8X�d ��q3_o"j R�� x��13���3D�#T'��M�@�R¤@§+³ ¬ � �R��X���N"9P{7�8 v?�*��D�;�(8D�t�"&�!���!th�LDv;K�!"& x�5 �(*��T�`;�T�$P"&��

HA

L author manuscript inserm

-00243083, version 1

Ã)Ã

# "��}th�� :���!"j R�u#T�T�+�*#T'~D:"o����?�*# "9�O%# "9P(9#.13"&%$��LDE�T?�u�$�31*# �T�+�^�z���*r��T��*�m(j}(~�$�819# �T��u"&rK�m"& `�!"& R�!�A"��T�3D:}"&�a :�7�A�8(�D

�V_o_)B+�aR13"& R���k��(9r D:�� N(z�!�8(9�Kr:"�#2# "&t�@��e"�r�UGqLdV'�8(9 x\"�r�U�U+�&WKth"0�!���e"�# �$�8 GDv;�(*�!l��&�GDp;0(9��DE;+"07��t�;"};0(9�K# "&th�* | E(8DE�

"&rk#2"07.�E"& �t�;"`%�(3�T�+�*�5P{"0����V(&�R�:�&(S�V(&�R"&13�T(8Dv��"0�Kt�;�� 1*;K13"9@# �`�+"6D�PA����c��#T(9�T��*�zP'`���"&tz�}�@A���*1�D��*�� :� ��VrE(91�DE"� x|rE"&

P"&���# "��\(*���`13"&%$��LDE�T?�5���*1*# �/��jq���"&�!���>t�� Dv;K�����e���3D���(`(* :��(3# R"`(8D�;��w%�;�� N :� ��K"�r�rE :(91�D�@� :��"jrAD�;+��r:���K@+ 8q

½B¦�±#¶>¯�¯³R£µÁG�&D�;�5(j��"j19�T(8DE� "0�KP{�RDEt`�*���e;+"j v�!"&��(3#���� E@+��# ��?�*#A(9��K13"0%���LDE�T?�zr�@��1�DE� "0��T��%! R���K(3�T�.19"&�3DE :"0?�8 RR�T(3#:q

� "9P(3#I�V(9 E��� x�E���"&r�1�@�K@+#�(�DE�T?���6EDv :"&%���O��c$�{"��@ ��uR;�"&@#2�CP�u�7c��{#2"j ��*�m(jV�"��R�wP# �u�/����T :��1�Dz�!�8(&�@ :�*>"&r5P(j��3��# �T�A�

;"& ��!"&��(3#evDE(8D�@A���DE" P{� @{��*��(&a19"���?�(3 ���(�DE�*a�/���6vDE(*P#T� �;�T��%�(j�R"&19��(�DE� "&�ot`� Dv;�19"&%���LDE�/?�-(S�����7@ �"0�2�AR'�1*;+��(�DE :�T1

��� R"& R���8 R��& �(�D�;��8 GDp;0(S�K�!"& x� *�w�EDE(S�SDv(*��*"9@{ ��"j |#�"&1*(9#+�V(& E�+�8 R.�@1�;K(j\R�8 v@���;�"j ��!"&��(9## ��?+�*#�*q

! G@��6�ÉÍ,'*�C=&T,�?�4<?.(;8$N.*�,=(;4<:P8QL�6.C98$O 6.7�-uD'L�D9O;,.(;4µ:98�8J&@(+*=6TNT8;?M8+�'�$6�&#D�*98

f|;0�>���*1* R�8(&R�!"& 5�T��1* R�8(&R�!"$rY�*EDE �"&%���~(&�R"&13�T(�DE�*�ut`� Dv;a����13�Tr:�T1��K(3 v��8 R5;�(&5PA�*���~(j7R"&13�T(8DE�*��th�LDv;eD�;�> :� R�m"&r

����?�*# "9�A�T��%O;"& ��!"&��*�E�����A��������3DK1*"0����LD:�T"&�����T��19#�@A�&�T��%-"�EDv�*"3�A"& :"�7�/^(*���O13�� �DE(9�T�)1*(*��13�� x����w�)t�;+��1S;aD�;�C�"*DE� "0�$^"�r

1�@�`@A#�(�DE�w?�¡;"& ��!"&��(3#)�7c��A"��@ :�¡(*�+�s;"& E�!"&��(9#Oth�T��$"&th�;�(3?+��PA�*��� #T(3 v%0�*#/'�@A��*� �R�8X�l$��W�����qCf|;0� ED�@+�&'�"�r

:�7� :"$�3@+1�DE�T?�>(*��C�!���{vDE E@(9#brE(91�DE"& xz"9�� ��/x��r�"j �;"& E�!"&��3�E7���R�LD:�/?�!1*(S�019�8 �;0(&`�T��1* R�8(&R�w��%#T'm :�*# �2�*�~"&�m�K(8Dp;���e(�DE�T1*(3#

�!"����*# .Dv;�(8D.1*"&�KP+�T��`�K@A# Dv���A# �`�K(3 v��8 R5�T�3D�"e(�R�w��%# �K� �0@(8DE�T"&� �TW���8��W����.(&��@1�;u�T�+���T13�*�� :"0?�T���K%� :��(8D��� .� ��8���21�DE�T?�

�"&th�� 5D�;�(3�a19"&���2���8 �(8DE�T"&�O"&rh�T�+���T?�� �9@(3#��K(3 v��8 R �TW�0U �8q�[�"j zP ��8(&ED�1*(S�019�8 R��D�;��t`�*# # �{�*EDE(SP#T�/�;�*�o :�7� :"��9@1�D��T?�� :� ��

rE(31�DE"& R�(* ��h��(3 �#w'e(*%+��(8D\�!����(9 :1�;�*�+�&@A# #T���+(3 :�LD�'��#�(�D:�z(*%�`(8D\rE�T xED|r�@#T#D��8 ����+ :��%���(*�+1*'�A#T(8Dv��(*%�z(8D\(*�&'!PA�T �D�;��#�"0t��+(3 :�LD�'

(*�!"&�$% �+(3 :"9@{^th"&�!����(*��)#T(�DE�m(*%�m(�DK�!���+"3�+(*@{R�&q\45��%0(9 :�&�T��%��7c{"&%+���"9@{�;+"j ��!"&��(9#��*rEr:��1�D:"& R��5�@1�;)(j �z,����(*�

�T��1* R�8(&R�*�~ �� R�Ct�(j`"9P{7�8 �?�*���|�6��A�*1*�T(&#�#/'�r�"j �th"&�!���a13"0�SDv�T�&@{�T�$%^DE ��8(�DE�!���3D51*# "�7�hD�"eDp;�>�!���"&�(S@{����E��*�>r:"& � ���?� ��t

�R� �j��E��q����m x��#T(8DE�2"&�^Dv"uHh4�fZ�|(� :��13���3D5�!�RDE(&��(*��(3#T'7� ` :�7�{"& �Dv�*�~(S�a�T��1* x��(j��*�~ ��/��a"&r��3qL��dCrE"& hd�'��(3 x`"&r�@{7��"j ��!"j R�

�TW�����q|fN;�� >�"*DE�2"&�O;0(&>(3# �"=P{�*���«th� ���*#T'o@{7�*� r�"& K]�_��`�.(C;��T%�;�� `PA"&��C�������LDv'aPA�*�T��% (&�R"�1*�T(�D:�*�oth�LDv; (m# "&�$%�8

�����"&%+���"9@{��<¤�� Â����8(9 :#w'!�!����(3 �1*;�*�$�(9 :�LD�'�+(*���!#T(�DE�5�!���A"3�+(*@{R�*�|"j .�7cA"&%���"9@{Z;"& :�!"0�0(9#G�7c��A"0x@ R�jg9Hh4�fo� :�7?�*�3D:|D�;�

�!���"&�(S@{R(9#b����1* R�8(&��>�T�CP{"&�+�e�$���$7�LDE'm(*�+�eD�;&@{}���*1* :��(�R�*5DE;�> :� ��a"jr�;�w�arE :(31�Dp@ :�*��t5;�� R�8(&z� :���!���+"&�(*@AR(3#|@{R��"&r

��,�7��(3# R"C(3rEr��81�D:zP+"&���# "��`(*�+�~ ��*�3@+13�*5DE;�> :� ���"�r�;�/�arE :(31�Dp@0 ��!�TW�$d���W� � ��q�f|;0� zP"0��K� �"*D:��1�D:�/?���8r�r:��1�D��T��1* :��(j7�*

th�LD�; �z,)��"�7��(*�+�`� :"9P(SP#T'!(3# 7"Kth�LD�;u�9@ �(8DE�T"9�e"�r|(3�&�!�T�+�/vDE :(�DE�T"3�Ai$P{�RD D��8 |� :"*D��81�Dv� "&�KPA�*�T��%e"9P{7�� :?+�*�!�T��"j#2���8 \t`"&�!���{�

¨ �l¤��3D�;�"����t�;+"�th�� R�bD�;+��13#2"07�*EDADE"`�!���"9�(S@{R� �TW+� � ��q

��;�2# ��DE;+�`@jDE� # �LD�'m"&r�%# "9P(3#|13# �w�� 1*(9#N�K(3 v��� xz"jr5�*EDE �"&%�*�m�7c��{"��@+ :�K;�(&5P�*���a�*EDE(SP#T� R;�*�C�T�uP+ :��(jED�1*(*��13�� 5(*��

"�ED:�*"9�A"& :"�R� ��A#2� D2DE# �zth"& E��;�(jIP�*���u��"&���DE"����xD��� :�!�/��h�TrND�;+��'e(3 ��5@{R��r�@A#G�T�>@��$�8 REDE(*�����/��%VD�;+�h�*rEr��*1�D:�"jr.�*EDE �"&%����"��

HA

L author manuscript inserm

-00243083, version 1

Ã�Å

P :(9�w�-r�@���1�D:�2"&���T��%Gq.f|;0� ��!�RDE;+"���"&# "&%�'�;�(j�"9�#T' ��@{ED}P��%&@+� DE"OPA�m(*���+# � �*�)�T�OD�;�m(3 ��8(O"&r!19�8 R�7P :(9#�r�@��1�Dv� "&��T�$% D:"

��c+(3�!�/��K13"&%$��LDE�T?�>��� �"& :�$�8 5�T�eDv;�>�*# ���� :#T'��P�@&DbD�;�� z :�*���(3 �1�;�� z# �T�!�LD:�*��th�LDv;~ :��%�(3 ���P"*Dv;eDE"!Dv;�K13"0%���LDE�T?�>r�@�+1�DE� "&�

R�*# �*1�D��*�!(S��hD�;+�h�*EDE �"&%�����V(9 E��� x5EDp@��� �*�AqAB$�!�LDE;�¤@§$³ ¬ �A :�7�"& �D��8�>r:"& �jl>�*# ���� :#/'e�+"&������!���jD��*�>th"&�!���KDE;�(8D\(S�e�T��$��c{�

1*"&�KPA���+�T��%C�!���$vDE E@(9# �� :�7� :"&�9@1�D��T?�*��(*�����+;�'R� 1*(9#N�K(3 v��� xz(j�R"&1*�T(8Dv�*�uth�LDv;��*EDE �"9%����#2��?�*# h�<¤�� Â���P+"j�0'~�K(j�z�T��$��c�:�

t�(j\ :�*#T(�DE�*�YD�"zP{�RD D��8 ��A�� :r:"& ��K(*��13��"0��Dvth"`?�� EP(9#jDv(j�� � W+��X��q�<K"K�T��&�T?�2�3@+(3#+�K(3 E�+�8 b�;"&t`�*�h(5�+(8D DE�� E�!"$rk(&�R"&13�T(�DE�T"&�{

th�LD�;!13"9%��+� D��w?���{�� :rE"& ��K(*�19��(j\1*"0�$7� ED����SD�(&\�&� �YDp;� \13"&�KP�/��*�K�T����7c{�$�T����T1*(�DE�T��%�D�;�(8DAD�;+�Y��r:r��81�D�."&rN�*EDE :"0%���!"&�KP E(9���

�V(9'OPA�C�!"j R�C(*���+(3 :�7�3DKtz;���aD�;�m1�@+�h@A#T(8DE�T?+�m�*rEr:�*1�D:�"&r>��c��A"��@ ��~(9 :�m��?�(&#�@+(8DE�*� �TW��X ��qbf|;�� �(3# R")�@+%�%�*ED:CR"&���

�T�3D:�� E�+#�(S'!PA�xDvth�*���u# "&�$%$�TD��� :� EDE E@+1�D�@ :(9#G1�;�(*�$%�6�(S��e�;"& �D:�TDv�8 ���(91�DE�T?�(8DE�2"&��(3#��!�*1*;�(*�+�/��!*q3<K(S����s¤@§$³ ¬ �G(9#/�"! :���+"j �DE�3�

D�;�(8D\��(3 :#w'u�@ E%�� 1*(9#��!���"9�(*@{7�zt�(&�(j�R"&1*�T(8Dv�*�!t��LDv;!�A"�"� :�� .1*"&%����LD��T?��r�@+��1�D:� "0�^���T�uR;"& �DkDv�8 v��?�� EP+(3#��!���!"& :'>P@&DN��"*D

�T�e(�D DE���3DE� "0�VDE(&��R�.�T�e(!vD�@�&'�th�LDv; �8���e'"9@��%>�(8Dv� ���3D: ����d��q$���e(K# "0��%�LD�@���/�0(9#kEDp@{�&'u�w�19#�@+���T��%u�������{"�ED����!���"9�A(*@{�(3#

th"&�!����|�&@{#2#��w�(9 :�LD�'m(*��m#T(�DE�>�!���"&�(S@{��>th�� R�!(&�R"&13�T(8Dv�*�Cth�LDE;aR�T%��+��r��T1*(*�3D:#/'�# �37`13"&%&��LD��T?������13# �T�+�!(8D5rE"$# # "&t @��a(&

�!�8(&�@ R�*�>P'u1S;0(9��%+�6z�T�u_a_«B�b��t�;�T1S;�x@%�%+�6ED�.D�;�(8D�(K;��T%�;+�8 5# �Tr:�RD��T�!�6�k�0(�D�@ �(3#���c$�{"��@ ���DE"C�6EDv :"&%���C�/�(j�R"$1*��(�DE�3�

th�LD�;e#2�3�.(S%�3�� :�*#T(8Dv�*�!13"0%���� D��T?�z���*13#T�T�� �TWN�8���q �.Dv;�� xZ�"��R�wP{#2���K(3 v��8 RND�;�(�DN13"9@#2�!�T��r:#w@A���13��;"& :�!"0�0(9#Ar�@�+1�DE� "&�e�@+13;

(j|(*%���(�D��!����(3 :1�;+�6�0�&@�KPA�8 |"jrADE"*DE(9#��+ :��%���(*�+1*� �6.�� R�*�@#LD��T��%K"j ��"*D����!#T�T?+�.PA�� �D�;R�:�$#�(91�DE(8Dv��"0�$�0;�(*?����"*D�P{�*���!�7c��A# "� ��*�h�T�

D�;�� �ED�@+�&'Gq9yh#LD:�� E��(8Dv�T?�*#T'�+4��T1S;0(9 :���¤@§^³ ¬ �+;�(*?����w��?+�3EDE�T%�(8Dv�*��D�;�5(j��"�1*�T(8DE� "0�KP{�RDEt`�*���!13"&%��+� Dv�T?��r�@��+1�DE� "&�!(�DN(*%��* �j�\�����

�8d��$W�&�&(*���`U�z'��(3 R\(*���YDv�T�!�T��%K"�rAD�;���!���"&�+(*@{R�I@{R�T�$%V(h,I"9cK� :"9�"& �Dv��"0�0(9#+;�(3�*(3 ����!"$���*# \�T����d�l&W`th"&�!���!rE �"&��Dv;A�

]. :�LDE� �;��8X&U��P�T �D�;a19"&;�"j �D�q�Hh�w%�;�� `13"&%��+� Dv�T?�uR13"& R�*Kt`�* :�u�;"&tz�~D:"CPA��(j�R"&1*�T(8D��*�mt��LDv; #T(8DE�� `�!���"9�(S@{R�u��th�LDv;~D�;A�

EDE �"3�$%�6vD���rEr:�*1�D.�/�~1�;� # �0;"�"���13"0%���� D��T?�z�A�8 �r:"& ��V(S�019�*� � WN�$� ��qA,."9%����LD:�T?+�YD��6vDE�T��%ut`� # #�P{�` :�7�A�8(�D:�*�u�w�!Dv;� �ED�@�0'~(8D\(*%+�

d��}'��(3 x7�AR"hD�;�(�Db�LD|t�� # #�P{�5�+"07��wPA# ��DE"����RD:�� ��!�T��zt�;�RDE;+�8 \th"0�!���ut�;">13"&�!�K��(3 �#�'KD:">�!���"9�(S@{R��(9 :��(�D|%0 ��8(�D:�� . :� ��

rE"& b1*"&%$��LDE�T?���$�*1*# �T��*�A�@�%�%+�6EDv�T��%hD�;�(8D|1*(*@{�(3#ArE(31�Dv"j R\1*"&@# �`P+���w�K�{#T(319�5# "&��%KP�*r�"& :�.D�;��"0�$7�RDN"�rGDp;�513#T�T�K(j1�D��� :�T1�qAB$@1�;

# "&�&%�D:�� ���� �"0x�{�*1�DE�/?�YEDp@��� �*|� :"0?� ����(��!"& :��(*���+ :"9� :�T(�DE���!�8(9�."&rN��?�(3#w@(�DE�T��%�D�;�I�{"�����PA# ��(j�R"&19��(�DE� "&�\"&rN19"3%$��LDE�T?A�

�&'Rr�@+�01�D��T"&�at`� Dv; #T� r��KDE�T�!�C�6EDv :"&%���O��c��A"0x@ :�*��D�;�(*�a R��DE �"0x��81�D��T?�uEDp@��� �*}t�;�T1*;a(9 :�u�@�P ����1�D�D�"m�!���!"& �'mP{�T(jVth�LDE;

:��%�(3 ��YDv"VR��# r� :�7�A"j �D�"&rG�K(3 v��� x\"&r�# �Tr:�RD:�T�!�5��c��+"0x@ R�jq

f|;0� (j�R"&19��(�DE�T"&��PA�RDEth�*���s# �Tr:�3�TDE�/�!��;"& ��!"&��(3#O�7c��A"0�@ ���(S�� y�� ;�(&� :��13�*�/?�*�s# �67�(8D2DE���3D:� "9� D�;�(3��Dv;�

:��#T(8DE� "0�$�;��w�ath�LD�;�x@�P{�E1*#2�T��T1*(3#\13"&%$�0�LD��T?�>�&'Rr�@�+1�DE� "&�Gq�y��~(j7R"�1*�T(8DE�2"&�uPA�xDvth�*���C�(3 �� Dp'~(9��uy��¡;�(j�PA�*���� ����A"� �Dv�8�C�T�

�8���ot`"&�!���-t`� Dv;)(O�j�T(9%���"��� �"&r!y�� 1*"&�K�(9 :�*�mD:"�� �jXO1*"&�3DE �"�#5th"0�!���-th�LDv;"9@jD>�����!���jDE�T( �TW|��W ��q�BjD�@+��� �*u"&r�Dv;{�

(j��"j1*�T(�DE� "&��"&rO�T��1* R�8(&R�*�� ��/���"&roy���th�LD�;�(3�0?0(9��13�*�¡(*%���(�Dm�!����(3 �1�;��(9���(9�3?�(9��13�*��(S%��(8Do�!���+"3�+(*@{R��(* :�

�T��13"&��19#�@AR�T?�*�A"&�+��vD�@�&'e�;+"&th�T��%!(z�"�R�LDE�T?+�Y(&�R"&13�T(�DE� "&�Kth�LD�;!(S%��"&r|�!���0(9 :1S;��P�@jD��+"6D�th�LDE;!(S%�5"�r|�!���"9�(*@{�� �7�8��X�:�

(*��"*DE;+�8 5�;"&th�/��%!D�;�K"9���A"07�LD:� �R���8� �:��t5;�8 R��(j5"*Dv;�� YED�@+��� �*5r:"9@+�����"u�*rEr:�*1�DIr:"& ��*�LDv;�8 �rE(31�DE"& �R����W����� � ��q�y5�~�*(9 :#T�T�8

HA

L author manuscript inserm

-00243083, version 1

à �

"&���RD\"&rN�!���"0�(*@{��5t�(j.r�"9@���!�/�!th"&�!����(8D| :� ��e"&r\�����!���jDE�T(&�;¨ �l¤��+t��LDv;!(��+"0�� D��T?�5rE(9�!� #T'>;��/vD:"& E'�"&rb��� 7�8(&��*�$P�@jD�D�;��

t�(jC�+"6D�r:"9@�����T�-D�;"�7�Oth�LDv;"9@jDu(�rE(*�K� #T'�;� ED�"& E'�"jrC�����!���jDv��( �TWN�8� ��q�Hh"&th��?�� x�`�LD��/=�"*D�1*# �8(9 utz;�xDv;�� m�8(9 :#T'

�!���"&�(S@{R�5� ND�;+��1*(*@{���"& kD�;��513"0�$7� �9@{���+13��"&rGD�;+�5y����+(8D�;�"�#T"&%�'Gq9y��+"6Dv;�� ZvD�@�9'e"&rb���$���.th"0�!���!(3%+�*�!d�d`'��(3 R.(S�0�

"&?�� x��@AR�w��%�(&z�V(9 E���� x`"9�#T'~(9%�K(�D��!����(3 :1�;+�!(*�+�u�!�S�"9�(*@{��6��r�"9@���(^��T%���TrE� 1*(S�SD5�/�01* R��(jR�>�T�~ ��/��m"jr5�������*�3DE�T(u�T�

th"&�!����th�LDv;-��(�D�@ E(3#z�!���"9�(S@{��m(S��«�!"j R�o x�7� �"��9@1�DE�T?�='��(3 x�(*����t�;+")th�� R�m(3# 7")y5�A"j�εU�1*(3 � :�T�� x*qN<}"��@+1*;

(j��"j1*�T(�DE� "&�`t�(j\"9P{7�8 v?�*�h�/�K�"&���1*(3 � :�T�8 R �TWN��U ��q

½B¦ ±H¶+¯�¯³R£[ÁG�}�&@��!�� R"3@A)ED�@�$� �6«�@�%�%�*EDuDp;0(�Dm(�1*"0�KP�T��*���T��$��c� R��r:# ��1�D��T��%�# �Tr:�RD:�/�!��1�@�`@{#T(�DE�T?���*EDE �"&%���

��c$�{"��@ ��6�$�K(9'V19"9�$vD:�LD�@jDv��(z�!"j ��Y7�T%���� rE� 1*(S�3D����xD��� :�!�/�0(S�jD�"&r�13"&%&��LD��T?��r�@+��1�D:�T"&�+�T��%K�T��Dv;�5�*# ���� :#/'�D�;�(9�K(hR�w��%# ���!(9 E���8

�E�@1�;K(j\�N4�fb��qSHh�7��13�*�3Dv;��1S;�(3 :(91�DE�� :� R�LD:�T13I"jrAD�;+�Y ����+ :"��&@+1�DE�T?�I�{�� :� "$�`�!�8 R�LD�r�@ �Dp;�8 \�7c(*�!�T��(�DE� "&�K(j|�"*D����3DE�T(3#+�K(j v��� x

"&r�# "&��%�TD��8 �� �7c��A"��@ :�KD�"m�����"&%+���"9@{>�6EDv :"&%���Gq�Hh"0th��?�� x��D�;��uED�@�$� �6}13"&�+�3@+1�D:�*�uDE"o�&(8DE��;�(S?��r:"&1�@{7�*�a"&�a"&�+#T'a(

��K(j#T#��j@+�`P{�� b"$rN :�7� :"$�3@+1�D:�T?+�Y#2��r�����?���3D:���%����� :(9# #T'!(S%0�5(�D��!���"9�(S@{��5"& �(*���K(*%�5(�DN�!����(9 :1�;���Nt`� Dp;"9@jDN19"&�R� ���� :�T�+%

"*DE;�� \�����"&%���+"[email protected](31�Dv"j R��E�@+1�;!(jI�!���EDE E@+(3#A1�'�13# ��;� EDE"& E'�&DE"*DE(9#+� :��%���(S�019� �*��+#T(31�DE(�DE� "9��N(S��!�7c{"9%���+"&@{.rE(91�DE"& x��@1�;

(j��5,�\"& �(*�3DE�T�*EDE �"&%���!��rEr:�*1�D�"j R.��(j|� �D�;���1*(j7���/�h;"& ��!"&��5����R�LD��T?��1*(*��13�� N"& N�����"0�!��DE :� "�R� R��;0(S?�.PA�*���K���%#2�*1�DE�*�Aq

��6.?=-sO;D.&�4�6.?�,�?�C�7>D=(+D�*98QC'4<*98J-�(;4�6.?=&

y��A# �RDE;�"& :(O"&reEDv :"9��% ¨l¦ ¥@¨»§l£}«-(S�0� ¨l¦ ¥@¨t¥@«���c��A�� :�T�!����DE(3#z��?�T�����13�o1*"&��?�� �%�uD�"-�@����+"j �D!(o�"�R�LDE�/?�m :"�#2�a"&r

�6vDE :"&%+���$}"&�C?0(9 :�T"9@{`�+��@ �"*DE :(S�$��K� D2D:�� h�'ED����}`(S��C"&�m��7@ :"&��(9#br�@+��1�DE� "&��/��%GqGf|;��e�*EDE �"&%���m�T��r:#w@A���13��"9��19"&%���LDE�/?{�

r�@���1�D:�2"&���T��%!� \(3# R"K�@�%�%+�6ED��*�zP'`%������� N���Tr�r:�� x�7�19�6\�T�K13"0%���� D��T?�I�{�� :rE"& ��K(3��19�Y��r:���!(9# �3|�A�8 �rE"j ��!�w��%`P{�RD D��8 |"&��Dv(jv�\"�r

?�� EP(9#��!�*�!"& �'u(*��ur��T��`�!"3D�"& �1*"�"& R�&�T��(8DE�2"&�u(3�����V(&# �3Y�{�� :rE"& ��!�T�&%uPA�xD D��� Y"9�u�A�� :13�7�jD�@+(3# �E��(�DE�T(3#ADE(jx�$���q{,I"&�K�A(3 :�w�&%

��� :r:"& ��K(*��13�u(91* :"��>"& `P{�RD�th�*���)19"&��&�LD:� "0�$>(&�R"&1*�T(8D��*�at`� Dp; �$��rEr��8 R���3Dz;"& ��!"&��(3#5��c$�{"��@ ��67���@1�;O(j}��;�(j��6>"&rYDv;�

�!���{EDE v@(3#A1�'+1*# �6���E�@ v%0�21*(3#T�N�!���+"&�(*@AR��(*�+�K?�(3 ���"9@{��7c{"0%���"9@{I;"& ��!"&��(3#G�*rEr��81�D�"& xI(3# R"ex@�%�%�*ED:I(��"��7�wP{#2���*rEr:�*1�D|(8D

# ��(jED\"9��?�8 vP(3#��!���!"& �'�+P�@jD�D�;�� It�(jI�"*D\rE�� ��!#T'������!"$�$vDE :(�DE�8���$D�;�`�8r�r:��1�D:IP{�*�w��%u�"&�!��Dv�T�!�3��!"����*ED."& \t��LDE;�# �T�!�LD��3�

1*# �T��� 1*(9#! :�*#2��?0(9��13�&q�f|;�-7��(3 :1�;�r:"& m1*"&�7�/vD:���3DC(j��"j1*�T(*DE�T"&�=P{�RDvth�*���������"0%���"9@{O�*EDE �"&%����#2��?�*#�o(*���13"&%$��LDE�T?�

r�@���1�D:�2"&�K;�(j|P�*�������+13"&��13#w@{��T?�*�&P�@&DN�LDN�;"9@A# ��PA���!���jD�� "&��*�5DE;�(�D��!��(j�@ ����!���jDN"&rN���+��"&%���"9@{I�6vDE :"&%+���!�/�D��*1*;$�0�21*(3#T#T'

���TrEr:�T1�@A# D���(*���C� D�� 5@$�1*# ��(3 �;"&t�7�� E@+��# ��?�*#�z�K(*'~ R��r:# �*1�D�# "&1*(3#�P :(9���m�*EDE :"0%���~13"0�019���3DE :(�DE�T"&�`"j �;"0t�th�*#T#N(uR�/��%�#��

�!�8(&�@ R���!���3D�� \13"& : ��*#�(�DE�*�`t��LDE;K1�@�`@A#�(�DE�T?�5�*EDE �"3%+���!��c+�"��@ ��jq

����DE;+�Y"*Dv;�� N;�(*�+�0�$�LDN� .EDE�2# #�@+��13# ��(3 |(j�DE"zt�;�RDE;+�8 \�6vDE :"&%+���K;0(&\(5� ���?���3DE�T?����r:r��81�D|"&�!�����!���jD��T(��T�!��A� D��5"&r{Dv;A�

�&@�!�� R"3@AevD�@��� �*>�A�8 �rE"& :�!�*�Aq���;�� R�8(&>�!"�EDK"9P{7�8 �?�(8Dv� "&��(3#5ED�@���2�6�19"&��9@1�D��*�O�T��Dv;���8�o#�(&ED`'��(3 R��<¨ �l¤��bD�;��C�!"�ED

HA

L author manuscript inserm

-00243083, version 1

à �

:"9P�@{vD�"3�+�3R��13"&�7�/vD:���3DE#T'!�/��&� 1*(8DE�*�`(�UN���El���� �$�81* R��(jR�*�K ��/x�!"jr|����?�*# "9�A�T��%Ky���(9�!"&��%`Hh4�f=@{R�� x��9D�;��� R��13���3D� R�3�@#LD:

"&rkDv;����H`�E_)Bu��� �>�"*D.�;"0t�(*�$'^R�T%$��Tr:�T1*(*�3D.��r:r��81�D\(3r D��* �d+q W!'���(3 R�"&r.,.�N�mDE ��8(�D��!���3D\(*�����?���u�T��&� 1*(�DE�*�!(�Dpth"��rE"�# �

�T��1* R�8(&R�a�T���$���!���jDE�T(-�E�*�7���3DE�T(3# #T'�?�(jR1�@A#T(3 u�&���!���jDv��(&�5P$@jD>��"6D>y�����(9r DE�8 �UGq W�'0��(3 RC"&rVDv :��(8D��!���3D�"�ru,.�|���A_aF�y}q

,\@ E ����3DKDv;�� :(*�+��@jDv� 1mDE :�T(3# C(9 :�m@+��@�LDE(SP# �Or:"& !D�;+� �$�xD��31�DE�2"&��"&r���7@ R"3�+ :"*D:��1�DE�T?+�)�*rEr:��1�D:m"&r�H`4�f.��1*"9���T���� R�T��%)DE;+�

�"9��@#T(8Dv� "&��EDp@��� �*�!�pth"&�!���!(*%+�*�!��d}'�8(9 x\(S�0�>"&# ���� x�$?�� �'!rE(3 \r� �"&��D�;�5�!���"9�(S@{7�Y(S���D�;&@{IrE :"&��Dv;��@{�@(9#A1*# �T��T1*(3#

R�LD�@(�DE�T"&���:��(*��>D�;���9@ :(�DE�T"&�����"���*��(S��!D�'&�A�e"&rIHh4�f���"& :(9#b,.�|�-(S�0��_aFAy`��tz;"���}���@+ :"9� :"*D��*1�DE�T?�}� :"9�A�8 �DE� �*z;�(*?A�

���?�� �PA�*���! :�*13"9%��+���9�*�K(*��`tz;"����R� �$�3�E��rEr:�*1�D:.�v�6��A�*13�T(9# #T'K1*(3 :�&� "0?0(&R1�@#T(3 ���13"9@# �zP{�z��cjD������/?�jq9f|;0� I�/ �9@{�LD��Y�$��rEr��8 R���3D

rE :"&��"9P{7�8 �?�(8Dv��"0�eED�@���2�6I�T�!t�;�� 1S;Kth"&�!���KPA��%�T�KHh4�fm'"9@+��%�� x�$(8DAD�;+�.�A�8 ��T�!���"&�(S@{R(9#��A�8 �� "����$(*��z@{7�T��%!�E�*��{�91*�T(3# #T'

�T�K��@ :"9��*����(8Dp@ :(9#{�DE�� :"��2�0|tz;"���I��;�(3 E�K(319"��&'���(9�!�T1�� E"9�{�� �DE�2�6\(9 :�.�+ :"9P(*P+#�'K�!"& ���rE(*?+"j �(*P#2�jq

��������'!�;"& �D:��13"&�!�/��%h;�(&|� :"9P(SP#w'hPA�*����Dp;��r�"�1�@{\"&�K# (8Dv�6�v"3�7�xDN�2�A"�EDv�!���"9�(*@{�(3#T��;"& :�!"0�0(9#1S;�(*��%�*T¨ �l¤���(�DG(

DE�T�!�>t�;����DE;�}���@ �"�����%����� :(�DE�T?�`�+ :"�19�6�z;�(&�(9#� ��8(9�&'CP��%&@�~(9���Cth�LD�;"9@jD\DE(S��T��%m�w�SD�"u(91*13"9@�3D5�T�+�j�/?� �9@(3#\# �Tr:�3�2DE�T���

��c$�{"��@ ���DE">;"& ��V"0�0(9#�?0(9 :�T(*P+��#T�LDv'�q&f|;�� R��� .�+"&t��"0�!�h19"&�h�A�*# # �/��%e��?�2�����13�.D�"!�@+%�%�*EDGDv;�(8DN19"&�`P{�T���T�$%VD�;�`�*rEr:�*1�D�."�r

1*# �T��� 1*(9#/�� ���� �"��9@1�DE�T?+�6��(*�+���!���EDE E@+(3#���?���3D:�th�LDv;��T�u(!1�@+�h@#T(�DE�T?�K�7c��A"0x@ :�`�!"��$�*#N�T�3D:��%� �(8DE�w��%u(3#T#AD�;�`1*;�(9 :(31�Dv�8 ��/vDE�T1j

"&rZDp;�! R�7� :"��9@1�Dv�T?�K�A�� :� "��C(j�th�*# #\(j`�7cA"3%+���"9@{`;"& ��!"&��(3#\�*rEr:�*1�D�"& x��k�V(S'~� �"&?� �$�K(��!"& x�}@{7�8r�@A#N(*�$� :"&(31�;uDE"!Dv;A�

@������ xvDE(*�����T�$%^"&r�DE;+�K�8r�r:��1�D:5"&r�ED��8 �"j�2�0�"&�!D�;�zP :(9���Gq$[A@ �D�;��8 . ��67�8(9 :1�;u� ���*�*���*�� R��%�(3 ��j�/��%!D�;�z�{"��R�wPA# �`���Tr:r:�� :���3D��T(j#

�*rEr:�*1�D:�"&�u :� ��~"&r.13"0%���� D��T?�K�0'$�r�@��1�DE� "0�$��"�r�������"&%���"9@G�¥v± ���7c"&%���"9@{�(*��u�;"& �DT¥v± ��#T"&��%�TD:�� ����8rEr��*1�D:5"�r��6vDE E"&%���{�

�6x�{�*1*�T(&#T#T'a(8D�D�;�u1* �� D��T1*(3#\�A�8 R�T"��o"�r�Dv;�>�{�� :�T�!���+"&�(*@AR(3#NDE �(*�R�LDE� "0��q�y���(3#T'7�6V� :"0?� �&�T��%mPA"*DE;O���xDv(3� # �*�m R�7� :"$�3@A1�DE�T?+�

;� EDE"& :�2�6=(*���(3��� �0@(8DE�O# "0��%�LD�@���/�0(9#K�&(8DE()"0��19"&%���LDE�T?+�)����13# �T�+�a(3 ��O#�(91*��/��%Gq�_=@#LDE�TrE(31�D�"j ��T(3#`�!"����*#��P(jR�*��"&��(3�

��c+;�(*@{vDE�T?�5?�� ��t�"&rN(3# #�Dp;�5;"& ��!"&��(3#���?���3D:ND�;� �"3@+%�;"9@jD�D�;�5 :�7� �"��9@1�D:�/?��#T� r:���;+"3@A# �`PA���7c��# "& R�*�K�!"& :�.Dv;"& :"9@+%j;+#T'hD:"

� R"�#T(8D��bD�;+���+��'h;"& ��!"&��(3#+���RD:�� ��!�T��(9�SD�\"jr�19"&%&��LD:�T?+����� 7"� :���� x\�w��D�;�5�*# ���� :#/'�q9f|;0� \1*"9@A# �h(9# R"h#2�8(&�5DE"YDp;�5� �����3D:�Tr���19(8DE�T"&�

"&r�?&@{#T�+�8 �(*P# �5�@�P{�p%� :"9@��{I"jr�;"& :�!"0��6�E7�����LDE�/?�5th"&�!����$t�;+"`�V(9'`P{�5(8D�;+�T%�;K :� R�!"&rN�$��?�*# "9�{�/��%V19"&%���LDE�/?���'��K��DE"&�e

��"&�!D�;�zP(j��/z"&rND�;�*�T �#2��r��xD��T�!�K����$"�1* :�T�+���(�D DE�� E����q+fN;�� �th"9@A# ��"9�{����@��eDp;���A"��R�wPA� #T� Dv'~"&r�"&rEr��8 ��T��%!DE(3�T# "& R�*�KD�;�� R(*��T�3

P(j��8��"&�uED:�� :"$� �>;0"& ��!"&��**q$fN;����@�P# �T1`;��(&#LD�;u1*"&��� �9@A���13�*5"&rZx@1*;�(`� :�7?���3D:�/?�5� �"&%� :(*�!�`t`"3@+# �KPA�h19"&�R� ���* �(*P#2�

P��(3 :�w��%��T�!�!�/���D�;��� R" ���*1�D��*�K�T�1* :��(j7�*.�T�>y � � :��?�(9# �*��13�`����U>�!��#2# � "&�K�A�*"9�# �5th"& �# �&th� �$�5�V(9'KPA���@rEr:�� R�w��%!th�wD�;!y��

P�'~Dv;���!� ���$# �~"&r�Dv;��WN������13���3D�@ v' �TWN�8d �E��(9��m(3# 7"uD�;�C�T��1* x��(j��u�T�a�!���+"&�(*@AR(3#Ith"&�!��� �pt�;"C� R�*����3DE#/' 13"0�$vDE�LD�@jD��

(3 �"3@$�0�m��d�� "�r�D�;�5th�*ED��8 v�K�{"9��@A#T(8DE�T"&���\�9@{�.D�"`�"9��@{#T(�DE�T"&�!(*%��T��%Gq&�v�hD�;� �KqwBkqL�0Hh������� xR"0�K;0(&\� ��*�&� 1�D:�*��Dp;0(�Db�;�"&@+# �K(

��7@ :"9� �"6D��*1�DE�T?+�u�8rEr��*1�D�"&r5�N4�f P���6vDE(*P#T� �;�*���N�LD:Vth� ���*�� R��(3��@{����9@ ��T��%m�!���"9�(S@{��>13"9@A# �~ ��*�9@13�KD�;�>�&@+�!P�� �"�r

th"&�!���Ct�� Dv;uy���P+'u�!"& :�5DE;�(S�~"&��`�!� #2#��2"&� �TWN�8���q$y�D�(}�!"& :�`%����� :(9#�# ��?�*# ��]. x"&"&�$�!��'{�� �¤@§s³ ¬ ��;0(S?�K�*EDE�T�K(8D��*�KD�;�(8D

���*#T(*'�/��%V�$�/7��(j7��"&�7�xD�P�'K"&�#/'�D�t`"`'�8(9 x��01*"3@+# ���A�� :�K�LDN(��&��1* R�8(&����T�hy���� ���?�(3# ���19�.P�'K(8D�#T��(jED�W+��� �TWN�8l��q

HA

L author manuscript inserm

-00243083, version 1

à �

��"&�!���u��"}�"*DN(9 : :�w?�z(8D|�!���"9�(*@AR�5th�LDv;e� �9@(3#� :� ��u"&rb1*"0%���LDE�T?�`����13# �/���"& .� �9@(3#G�@AR13���jDv��PA� #T�LDE'hD�"�Dv;���*rEr:�*1�D�

"&ruHh4�fYq�f|;0�« :��(jR"&��t�;$'��"&�!�«th"&�!������*�S� �!"& R�O?&@A#T��� :(*P+# �mD:" ���@+ x"9�{x'1*;��T(8DE ��T1-��� R"& R���� x= :���K(j�/�$��{"$"j �#T'

@������ xvDE"�"���(*���(«�K@#LD:�TrE(31�Dv"j ��T(3#K(*�$� :"&(31�;��/�019"& E�"& :(�DE�w��%�"*DE;+�8 ��+ :�*��� ��"�7�T��%�rE(31�D�"& xm�E���&?�T �"&���!���jDE(9# �z%����RD:� 13�z"&

P� "&# "&%+��1*(9# �$¤�� Â��+?�(jR1�@+#�(9 brE(91�DE"& xR�|�/I R� �3@A�T :�*�Aq&y�D�DE;��� :�3R���3D�D:�T�!��DE;�� R��� �# �LD DE# �`�&(8DE(5DE"!�@��$�"& �DGDp;�67�z;�'&�{"*Dv;�67�3.(S��

r�@ �Dp;0�� hEDp@��� �*!�;+"3@A# �mrE"�1�@AK"&�uDE;+�e�/�SD���%� :(�DE�T"&�a"&r�(3��� �9@(�DE���T��r:"& ��V(�DE� "&�a"0�� R�7� :"��9@1�D��T?�>;� ED�"& E'Gq � �*�� :# �/��%�¤@§.³ ¬ �

:�7�"& �D��*�~D�;�(�DYDp;�u :� ��O"�r`�����!���jD���(m(S�����(3 ��8�o�!"& R��� :"9�"9@+��13�*�O�w� y5�A"εUOth"&�!���Oth�LD�;O;�T%$;�8 K ����+ :"&�9@{1�DE�/?�u'+�8(9 x

��1*(3#T1�@A#�(�DE�*�)(&!D�;+�a���Tr:r��8 R�7�13�o"&re(S%�a"&r��!���+"3�+(*@{7�m�!�T�&@{�(*%+�a(8D>�!����(9 :1�;���:�5tz;�8 R��(j��T���"&�-1*(9 : :�T�� x^�"�1*# �8(9

(j��"j1*�T(�DE� "&�)t�(&�"9P{��� �?�*� �TWN��U ��q\�v�)'�RD!(S�"*D�;�� eED�@A�&'�5�*EDE �"&%���O@{7�Ct�(&�(j7R"&13�T(8DE�*� th�LDE;-#2�6��1*"&%��+� Dv�T?�a�$�*1*# �T��

(*�!"&�$%εU�����%�(�DE�T?�5t`"&�!���!P�@&D��"*D

εU+�2�{"�7� Dv�T?�5th"0�!���kq�F�"6Dv���SD��T(3#��!�*1*;�(*�� ��}7�+�T�1*#w@{�$�T��%!1*(3 �"*DE� �K(8Dp;�8 �"��1*# �� R"�R����$P�'

t�;�T1*;εU��K(3'��T�3D:�� :(91�D|t��LDv;u�6EDv :"&%����(*��>13"&%$��LDE� "&��;�(*?��P{�*���u��?"&�+�*�e(S��!(9# R">t�(9 : �(*�3D\r�@0 �D�;��8 .�/��?�*ED:�/%0(�DE�T"&� �R�8��l��q

fN;��`��cA� ED����019�h"&r.���?+�8 �(3#A�+"j#/'��!"& E�+;� R�!�"�rb�|4��α

"j β�\1*"9@{#2�!(3# R">13"&�3DE ��wP�@jDE��D�"!(K�&� EDE�/�01�D.�@AR13�7�jDE�wPA��#2� Dv'e"$rNth"0�!�*�

DE"5D�;�.PA�����r:�T13�T(9#{�v"j �;0(9 E�Kr�@{#T�N��rEr:�*1�D�\"jr|�6EDv :"9%���{�i�(��"�����P+� # �LD�'Kt�;�T1S;h;�(j|�+"6D�'+�xD�P�*���K(3�$� �&@(8Dv�*#T'V�7c��A# "& R�8�Aq

[A@&D�@� :�! ��67��(3 :1�;mt`� #T#b(9#/7"C�T��?"�#/?�hDv;������?�*# "9�+�!���jD5"�r����tsB�N4�_ (*���mED�@�$� �6}"&rZDv;�*�T ��w�3D:�� :(91�DE� "&�mt��LDv;��N4

�@�PjDp'j�A�**q�fN;+�! *�T����(&# �=B�|4�_�t5;�T1*;)� �EDE�T# #�(91�DE�T?�*#w'OP�*�T�$% R"9@+%�;3D:���;�"9@A# �m� �"&?�� ���!Dv;��PA����*rE�LD:�"&rK�*EDE �"3%+���)t�� Dv;

:��%�(3 ���DE"`�"�EDv�!���"9�(*@AR(3#+;��(3#LDv;KP�@jD�th�LD�;!�!�T�+�T�V(&#A ��/x�{�ijDp;0(�DN� \�K(3�/�SDv(3�w��T��%KP+"&��������7�LDE'!(S�0�!7�� E@+� #2���A� ����$th�wD�;"9@jD

�T��1* R�8(&R�w��%hDE;+�Y �� ��e"&r�P ��8(&EDN"& \���+��"&�!��DE ���(9#A1*(*��13�� x�+(S���Kt��LDE;"9@jD�D�;��R� �$���*rEr:�*1�D:I(j��"j1*�T(�DE�*�Kt��LDE;!1�@+ : :���3DIB�N4�_ �<¤�� Â��

?���"9@{mDp;0 �"&�KPA"����KP{"$#�� �� (*�� ;0"*Dmr�#w@{R;+�6R��q`� Dm19"9@# ��D�;&@{o� �"&?� �$�)� �"*D:��1�D:�2"&��(*%�(3�T�ED=�!���"9�(S@{R(3#u�'$�h��DE"&�!��

"�ED:�*"9�A"& :"�R� ���1*(9 :�&� "&?�(j�1�@#T(3 5�&�/7��(j7�6��;+"j ��K"&��>�����{���+�����3D�1*(S�13�� x��(S���u(3# R"u19"&%���LDE�/?�!r�@��+1�DE� "&�GqAf|;�`� ��67���3D� ���?� ��t

;�(jK�@�%$%�6vD:�*�C(��&@�KPA�� �"�r5���T R�81�D�� "9�Kr:"& �r�@&D�@ :�>1*# �T��T19(3#\ :�*���(3 �1�;�q�MN(9 E%��hDE ��T(3# `(3 ��!�+"&t� �� �9@{�T R�8�uDv"m��c��A# "& R�hD�;+�6��

;�'&�{"*D�;+�67�3�th�LD�;�/�e(K�`@A# Dv� rE(31�DE"& ���(9#��!"����*#�t�;+��1S;VDE(S��*5�T�3D:">(31*19"3@$�SD\ R�7� :"��9@1�D��T?�z;� EDE"& v'^(S��>%����RD:�T1z� R�*�&�/x�{"�7� Dv� "&�

�T��13#w@A�j�/��%u�N4��A"�#T'��!"& v�;�� R�eSq�v�!DE;�Kr�@&D�@ :�K�LDI�V(9'u(3# 7">P{�`@{7��r�@{#AD�"u��cjD����0�C�@1*;u(>1�@�K@#T(�DE�T?�K ��/��u�!"��$�*#�P{��'+"&��

1*"&%���LDE�/?��rE(91�D:"& x�Dv"h�w��13#w@A���.�{x'1�;�T(8DE ��T1Y�$�/�"j R���� xSqH

AL author m

anuscript inserm-00243083, version 1

à �

��8$7;8;*P8;?=-s8J&

�R� � ��EDE�� :#w@+�����_�q �!q �0H�@ ��0� ��q M�q3�\�Dv :"9%���K :�*13�7�jD�"& x\�w��Dv;��;&@�K(9�Vr�"& :�7P :(9�T�V(S��5D�;�5 :�*#T(8Dv� "&��DE"`��7@ R"3�A�'1*;��T(8Dv :�T1��� R"& R���8 R*q}�º£}«@Â�� ¤v¶>£}«X´+¨[« ¬ ���������j����0Wd��8�E��l+q

�TW � � (3 �1*�T(j��B�7%&@ :(&��M.q _)qL�9y��*13"��LDE�T(&����qL����"9�,.(9 :#T"���$M�q M�q�<K�7@ :"9� �"*DE�*1�DE� "&�`P�'!�*EDE �(3�&� "�#Eq}�º£}«@Â�� ¤v¶>£}«>´>¨[« ¬ ���������j���� ��WX��E����q

� �� ]���;# �+,5q���6EDv :"9%���K(j\(�����@ R"9� �"6D���1�DE�T?��;"& ��!"&��&q���³^§�¡�¤#¥�� ¤v¶>£�«p±Hªv¨������������ &�$U������U�WAq�TU � �N;�(3"��$M�qL�3��@A��f�q ��q ��]. ��w�SD�"&��$4hq �!q9�bED� :"9%���K R�819���jDE"& b�@�PjD�'&�A�6\(9#��+;�(�(*���`PA�xDv(�13"9�3DE :�wP�@&D:�\D:"`��7@ R"9� :"*D��81�Dv� "&�

(*���`�T�1* :��(j7�*�`].13# ��W!�7c�� ��6�7�T"&�!�w�h�+ :�T�K(3 v'h;�w���A"&1*(9�h�(9#+��7@ :"&�*q}U�£B³;¨l¦E¡�¤#±6���������0���������j�0W�W�E�&UGq� d� �5@�P(9# � �!q ]�qL� �N;&@{�{HeqL���z@{���3qL�A4�(�@A��BGq ��q ��B�;&@�%�;� v@{�*�AF\q �3qL�A_o�8 �1�;���3DE;�(9# �8 R�A��q Ä'¤@§u³ ¬ �G�bEDv :"9%���e R��13�7�jD�"j .(9#w�;�(j�

�"*D|P{�RDE(j��� �(K1* ��LD:�T1*(3#�# �/���u�T�u�6EDv :(3�&� "$#/�p�!�*���T(8D��*�>� :"*D��81�D�� "&��(*%�(3�T�ED|P �(3�w�u�T� ��@ v'�q)��£�«>ª���³^§ ¬d� ª#³>² r ªv¨�� r � ��������&���������X�d&W�ElAqS����@�PKW�����\[G�7Pe�Aq

� �� ��(*�&%�+M�qL�$y5����� x��"&���Bkq �&� (* E���8 R�+_-q � � @{�DE(3r:7R"9�$���9q y!q9�bED� :"9%���! R��13�7�jD�"j .���N4���P�xDv(����+"j1S�"9@jD|�V�213�5 :��?��(&#A( :"&# ��r�"& .�N4.P�RDE(K�T���!�T%� �(8DE�T"&�u"&rb19"& �DE�T1*(3#���7@ R"&���T�VDv;�`����?�*# "9�A�T��%>P :(9���Gq��º£}«>ª���³^§ ¬d� ª#³>² r ªv¨�� r�� ������������������+l&����� �qS����@�P!W��������R(S�}�Aq

� l� 4�� ���V(S��+��q [bq �$H`�81S�$�{y!q M�q �+M|�8"&��(9 :�����3q ��q ��B$;&@������T��+_-q y!qL� � @{EDE(9r:�R"9����3q y!q���� R E@��&DE�T"&�e"&r.�*EDE :"0%���! :�*19���jD�"& P�RDE(K%���+�K�T�h�+(j�T R����(8DE�T(9#k#2�8(9 E���T��%u�T�ur:���K(&# �`�!� 19�jq)��£�«;ª���³^§ ¬+� ª#³>² r ªv¨�� rQ� ���������+���������X�X��$��U�����*q+����@�PW���&WK_m(* z��WAq

��� � B�;&@�%�;� v@{�*�NF\q �3q �|MN(*���*�N_�q �}qL�|_a�� :1S;���3DE;�(3#2�8 R�N��q�,."&�`�(9 :(�DE�w?����� EDE ��wP�@jDE� "0�a"jr`�*EDE :"0%���� R��13�7�jD�"j R��(3#w��;�(u(S��a�P�RDE(5�K4b<}y��T��D�;�� :(�D�1*���SDv :(3#$���8 �?�"9@{.�'ED����^q���¾�«>¯�¹�� ¤v¶>£�« ¬ ��� � �!j�� �������d$��l���WdAq

� X� Hh�� : :�/��%3DE"&�� �>q _�q ��Hh"9t�(3 :���|f�q �!q ��H�(*t5��T��� � q y!qL��4���P"9@{7R�T�� �>q _�q � ��@�"�*qL� �N;+����%�IBkq M�q ĺ¤@§P³ ¬ �N�\ED� :"9%���� :��13�7�jD�"j }�"�#T'$�!"j v��;� ��}�(*��«�*rEr:�*1�D:�"$r!�*EDE :"0%���) x�7�# (91*���!���jD>"&�);�w%�;{�v�����R�LDE'�# �w�{"9� �"6D����T�-1*;+"j#2�3ED:�� :"$#��T�th"&�!���Kth�LDv;V19"& :"&��(3 v'V�&� 7�8(&��&q�� i�¦X ¬ ����¤#²{������������ ���j�+X���l��El&UAq

�R�8�� ]. :(S�0�$�/�+_�q M�qL�+].�81S;�8 ��T�� �+M�qL� � ������(9 :� �+M�qL�+4.(31*1�;� �+_�q �$].�T(9�01S;�RD DE� �+y!qL�&<K(31S�V�T(&��+]�q ÄJ¤@§;³ ¬ �+yh��"�13�T(8Dv��"0�e"�rGDp;{��6vDE :"&%+���- :�*19���jD�"& �(3#w��;�(o%0���+�C�{"�#/'��!"& E��;� ��}�t`� Dp;���A"j �(3�&�T1oyh#T�*;�*�T�!�� �� ���� ���(jR�&q�U�¨µ«>ª ® ¤v¯ U�¨[« ¹ ® Á;±M¡�¤#±¾�«>¯�¯�¶d¦{���# � � ��$��%���&��d�� �+q

�R��� � �:R"��3�T��(9�&(j� �!qL�._o(3���j(&��_-q � �`"&��%���3qL�Iy��j(91�;� � �eqL�IHh(9 E(3�&(j�ZHeq � �5 :(S�0(S�!� � �>q Ä�¤@§�³ ¬ ��FG"�R�LDE�T?+�~(&�R"&13�T(8Dv� "&�P�RDEth�*���a(S�a�3EDE �"3%+���a x��13�7�jD�"& 5%����>�A"�#w'��!"& E�+;� R��(*�+�~F�(3 E���T�7"9�{� K�&� 7�8(&��>th�LDv;a�����!���jD���(+q>i�¶>£��&� ¤v¶>£�« ¬ �� � � +���j�&U���8�EdAq

�R��W � ��� � �eqL� �Y �(*��(*�!� � �!qL����(9�j(&���:�"$�6� �!qL�+yh�&(31S;� � �eqL�$<K(*��(jv;�/�V(&� �!q$�bEDE �"3%+���^ ��*13�7�jD�"j \%+������A"�#T'$�!"j v��;� ��}z�T��(8Dv�����3D:^th�LD�;�yh#T�*;�*�/�!�8 R� C�&�/7��(j7�6��?�(&R1�@#T(3 >�����!���jD���(o(*��O(9#�19"&;"�# ��(&�R"&13�T(8D����-�����!���&DE�T(q�'�¤v¯Q¤#¦^§)(¤v£�¨t³^§l£¾�«@Â^¦)'�¨1±H«>£B²{�*�������������$�����8X���W$WGq

�R�8�� �5 :(*��(9�K�/� �>q �&� (*�&@jDE(S�0� � �eqL�&��(9�&(j���:7"��6� �>q � �`(9�K(*%�(8DE(&� �>q �$y`�j(91�;� ����qL�&<K(*��(&�;��T�V(&� �!q�� ,.(S@{R(�DE�w?�z%����*��T�yh#T�*;�*�/�!�8 �� \��� 7�8(&R� ��q�� ¨ ¹>¹.«d¦�¡�«d¦R¤#¦½5Â;³�+,+v³R¨�-s³X±}± ® ¨ �����.���j�/ *�0�����8l���W��q

�R��U � _a(* v@�'�(*�K(j�$HeqL�$fb" �R� �$HeqL�$Hh(* E :�w��%3D�"&��A,�q 4�q ��B�(&:(S���/� �>q �$�E��@+�!�/� ��qL� ��;��&@+�V(&�+fYq ÄJ¤@§;³ ¬ �AMN(91��!"&rN(*�!(&�R"&13�T(8Dv� "&�"&rY�*EDE �"&%���u R�819���jDE"& �(9#w�;�(>%����`�"$#T'��!"& E�+;��/��e5(S��!DE �(*�R1* :�w�jDv� "&��(3#�(31�Dv�T?�LDE'�th�LDE;uy`#��S;�*�T�!�� ��&� ���(j7�jq � £}ª ®� ¤v¶>£}« ¬ ������������%108�&W+������U�Aq

�R�8d� _a(�D DE�T#T(j� �Kq _-q �+4��w�j�+�6���3q �KqL�+4�"3'3D Dv(j�+_)qL�+M�(3�w���(9#�(3�+FNqL�+M���;3D:�/�V(9��� �+fYqL� �5 E(*��(*�!� � �!q ÄJ¤@§^³ ¬ �AM�(31��!"�r|(j�R"&19��(�DE�T"&�P�RDEth�*���m(9�a�6vDE :"9%���m R�819���jDE"& u�`%����}�{"$#T'��!"& E��;+�/���(9��CFG(9 E���w��"&�� }�&�/7��(j7�!t`� Dp;a�����!���jD���(+q � ª@§1³2� ¤v¶>£}« ¬r ª#³>¦>²A�����������������j����W �j�E���+q

�R�8�� �`(3rEr:�*� �!qL��M�@� ��M�q �eqL� � �(3�9'� �>q �zB&DE"9��6� �!qL��_a"& �����5F\q\�bED� :"9%���) R�819���&D:"& a�^�"�#T'��!"& v�;�� R�e^(*��O :� ��-"&r1*"&%���LDE�/?�5�T�h�+(3�T ��!���SD��/�!"j#2���8 |t�"&�!���kq}U�¨[« ¬ �T±»Á$ª ® ¨l³^§l£[ÁG�*��������*%/������l$l�� �3WGq

�R�8l� _a(�D DE�T#T(j���>q _)qL�ZyYcA��#T�V(9�� �!qL�.4����$��6���3q �KqL�I].#�"0�KP{�� �%$��_�q ��MN�7;SD��T�K(*�� ��f5q ��M�(3�w���(9#�(&�.FNq ÄE¤@§E³ ¬ �����3D:�� :(91�DE�T"&�P�RDEth�*�����3EDE �"9%���- R�819���jDE"& O�~(S���aDE;+�a�7�{��T# "0�0U�(3#2# �*# �a"&r>(*�"�#T�w�A"3�+ :"*D:�*�/�-���/�01* R��(j7�6>D�;�m �� R�-"$r!rE(9�V�2# �T(3#yh#T�*;�*�/�!�8 �� \��� 7�8(&R���/�Kth"&�!���Gq��Q¤v¶>£�«d±#ªv¨�3=¤@§[§T�����������$���$�$Ud�� ��q

�R� � � [G"& x��*#�# �+,�qL�$�����K(3 E��$��qL�&y5cA�8#/�V(9�� �>q �$].# "&�KPA�� E%��_�qL�3��(S;�#�@+����$M�q �KqL� � @AED�(3r:�R"9����3q y}q Ä$¤@§+³ ¬ �+���&?�3EDE�T%�(�DE� "&�"&rN(V,Iy� ����A�8(�D\���KD�;�`"��*EDE :"0%���! R�819���jD�"& NPA�RDE(�%+������T�K�A(8DE�T���3D:Ith�LD�;>yh# �*;+�*�T�!�8 R� ���� ���(j��jq#i�¶+£"�� �¶>¯4(�¤#¦R¤@§ ��������&���� �j�0W��UGq

�R�8X� MN(*�`PA�8 �D:���6qL,zq �IH�(* E :� ����*q _�q �I_a(*�&�� �!q ��MN���K�!"0�$�IHeqL��,."&(8DE�*����3q ��,\@$�K�!�T��%�Iy}q Ä�¤@§�³ ¬ ��y� :��D�;�m�*EDE �"3%+�*� :��13�7�jD�"j R\�w��?"�#T?+�*�h�T�`yh#T�*;+�*�T�!�* x� \�$�/7��(j7�51� ¤v¶+£�«d±Hªv¨�3T¤�§[§2���������3�� ����3�|��X$���ElAq

�TW�� B�w��%�;��_-qL��_a�7'�� x����q _-q ��_a�T#T#�(9 :���+��q �3q �|B+���`�+��T�����3q ��q �Y?0(9 :�T(*�~EDv�8 �"�� �u���7� ��T?�(8DE�T"&�u R�6x@#LD:��/�^(> :�7?�� xR�wPA#��# ��(3 E���T�$% �/�K�(3�T ��!���3Dh(S��O13"&�`� �"&�!��7�*� 1�;+"�# �T��� E%+��1mr�@+��1�D:�2"&�)���)r����V(&# �oB�� �(*%&@�*����(9t�# ��') :(8D�*q$U�£|³p¨t¦�¡�¤#±6�� � ��+�����$����d�����W�q

�TWN� � � �wP�P{���4hq ]�q��|rErE�*1�D:�"jrI%�"&��(j�&(9#G;+"j ��!"9��` R���#T(913���!���jD."0�e�!��(jx@ R�65"&r|P(j�(3#Gr�"& :�7P :(9���u1S;"&# �T��� �%0�21hr�@+��1�D:� "9�Gq� ¤v¶>£}«d±Hªv¨[¤#¦Rªv¤3���������0�������&��X$���8� �q

�TW�W � _a�T# # �� x�I_-q _-q �.[A E(S�j�+# �w�$� �!q ]�qNf|;�*"& R�xDE�T1*(9#�P+(jR� >r:"& �D�;�^P{����*r��LDK"&r��A"�EDE�!���+"3�+(*@{R(9#5�6EDv :"&%���)�@�P{vDE�LD�@jDE� "0��qi765¹ ��(¤v£�«d¦$§l« ¬ � ��� � � ��� *��d �jl$�E���&UAq

HA

L author manuscript inserm

-00243083, version 1

à ¸

�TW�� � @���$#�(S;�,zq �0M�@{�*<uq ��qL��].�RD�;��(j�+,�q M�q ��?�(3 :�T(S�}EDv�8 �"j�2�h R��%&@{#T(�DE�T"&�!"&r��!"&�"&(9�!�T��5"9c{�T�&(j7�*��y�(*��K�E]O�K4b<}yh\�T�D�;�z�V(91*( �9@A�h��"& RR(3#� :(*�$;0�z(*��};�'&�{"*Dv;0(9#T(3�!�T1`�&@19# �*�Eqv�T±�Á$ª ® « ¹ ® ³R£}¯³Rªv« ¬ «)ÂvÁ � U�¤v£ ¬ � ������������������+Wl��8� �9WGq&����@�PW���&W �R(S�VW�U�q

�TW�U � B��!�LDv;$�IM�q �*q �|H`���0�$�8 R�"&�� �3q y}qL�|y5PA�*#�# ��,�q ��q �I].�xDp;�8(&��,zq M�q��NrErE�*1�D:>"&r ��?�(9 :�T(*��BjDE�� :"��2�0>(S�0�o4�(9#�"9cA�Tr:����C"&�FG �"6Dv�8�T��Dv;�(8D¡B�'&�3D�;�3�� �3�*�)f\ E(*���+"j �D:�O(S�0� �`��%0 �(3��� B+�8 �"6Dv"&��T���T��DE;�¬4�(S��;��45��%�� "&��"&r�_a(91*( �9@A�6*q� ¤v¶>£}« ¹.±»Á$ª ® «B¹ ® ³R£�¯�³Rªv« ¬ «@Â�ÁG���������+�����3�N���q

�TWd� 4.@��$� :��1�;3D:��4`qL�����`_a�T1�;�*#2�6�z[bqL��Hh�8 ��K(*����z]�qL�KB&DE :"9;�# �*�zy}qL�zMN(*��19�*#/�z_-qL�54�"&�!�*"�����q Ä�¤@§�³ ¬ �5<K�7@ :"&(91�DE�w?{�EDE�� :"��2�0Sg\�!"�# �*1�@#T(9 K�!�*1*;�(S�� R�!�"&rK(31�DE�2"&� (S��O�T�K�{#T� 19(8DE�T"&�>r:"& ��7@ �"3�AR'�1*;+"3�+;�(3 v�V(913"�# "9%�'GquU�£B³R¨l¦ �9¡�¤#± �U�£B³R¨t¦ �v¡�¤#± ��¡�¤#¥ � ���������&�� �08�d$X��E��l+q

�TW�� ]���;# �N,zq ��H`"j# �P+"��8 R��[bq+f|;��Kr:���K(j#2�!��7cm;"& E�!"&�+�!"��*EDE �"&%���~(&�(>����@+ :"9� :"*D��*1�DE(*�3D�qs¢$£�¤#¦>²+± �u� ® ³R£�¯³Rªv« ¬ � r ªv¨ � �� � � +��$/���&U$UN�8��UGq

�TWl� _a1*��th����\]�qwBkq�,.#T�w��T1*(3#\ R��?+� ��t��8� �g�f|;�>�!"�# �*1�@A#�(9 5(*���C��7@ :"&(*��(�DE"&�!� 1*(9#NP(&R� `r:"& ��*EDE �"&%���a�*rEr:�*1�D�`�T�^Dp;{�13���3DE �(3#$�0�� �?�"3@A.�'ED:���uq���¾ ¬ ¨l¦�i�¦+²R«>ªv£�¨l¦;« ¬�� � ¤@§1³R´>« ¬ ¨l±H¯h��� � � ��������8l�X$���ElAq

�TW � � ,."9'# �*���9q f5q �+F� :�T1*�*� �!q M�qL� �z�8MN"0��%�A_-q 4`q&y�#T�*;�*�T�!�� x� 5����R��(j7�&g�(!�&� 7"j ����� �"&rb19"& �DE�T1*(3#�1*;"$# �T��� E%�T1K�T�$��8 v?�(8DE� "0��qr ªv¨[¤#¦Rªv¤3��� ������$/���+����� �3U+�EX��+q

�TWX� ,\;�(*�$%$� �KqL� � "$# ���mFbq ��q=B�t��LDE1*;��T�$%��!���!"& :' �'ED����^��9@ ��T��%�# ��(3 E�+�T�&%kgC1*;�(*��%+�6��/���+(8D DE�� E��"&r�P �(3�w�(31*�RDE'�# 1S;"&# �T��� :�*# ��(j7���/��D�;+��;+���$�"�1*(9�h�$@{\(*���KEDE :�T(�D�@����/�V �(8D:�q ��� ¤v¶+£�«d±Hªv¨ ���.�������$/ &�+���������Edq

� ���� 4�� ��1*;+�8 R��4�"��7# �8 R��y!q ��H`(3r����8 R��Heq�B1�;�� �3"9��;� R����T(¡(*����"��*EDE �"&%�����E�v�/«D�;�� R��(S��(j��"j19�T(8DE� "9� 5 i�¶>£ � � £}ª ® ��T±»ÁJª ® ¨t³^§l£[Á��R¾ ¬ ¨l¦ �,�Q¤v¶>£�«d±Hªv¨ ����� � ����$��$0�+�&W�$�E� ��q

� ��� � _a( �x��th���(j�$_-q �!q �0Hh(* � :� R"9��3<uq M�qL��B1�;&t�(3 �DE�3��4`q �VqL�$].(* E���� x���3q M�qL�&FG(S@# �ABGq _)q$BjDE�� :"&� �`;"& ��!"&����!��DE(SP"�# �LD��6\(9 :�P(3 �P+� Dp@ E(8DE�*��# �T�+���!"$�3@A#T(8DE"& R\"jrAD�;+� � y�]Iy ��819���jDE"& 8q r ªv¨l¤#¦Rªv¤3��� �����*$/ �$�������&U�El+q

� �&W � ,.(SP0 ��8 �(3��4hq �3q ��<K(*?�(* : �"��N,5q ��q+FA :"9%�*ED:�� R"&��>�T�~?��LDE �"~�T��19 :��(jR�*�<}_��zyz�v��?"&��*� � �9H �5��"9�(9�!�T�+�K x�*#2�8(&R�!rE �"��EDE ���(�D�(3#AR#T��19�6\�/�h� �"��*EDE E@AN �(�D:*q �Q¤v¶>£�« ¹ ® ³R£}¯³Rªv« ¬ «)ÂvÁG��� � ���� �%����8l$d�� �q

� ���� _a"& :� �7�RD DE�*��_�q �����+FG(9"j#2"0�$f5q3�NrErE��1�DN"&r�1*;� �"&��T1��3EDE �(3�&� "&#A(*���z� :"0%�6vD:�� R"&��bDv :��(8Dv�!���SD�."&rN"&?�(3 ��T�*1�DE"&�!� �9�*�� �(8D:"&�`P :(9���K��"9�(9�K�T��.@$�jDE(*�+�YR�LD��6*q�� �#� ¤v¶>£�«+ª ® ¤v¯ ����� � ��0� � �$�N� �&lj�$� �j�Aq

� �&U � B�w��%�� x�A,zq y}qL�$4�"9%�� x�� �>q M.qL��BjD� :�T1��#T(*�+�0�+f5q _�q � ��"& R:(&� �>q _-q&�\�Dv :"9%���K� �"6D���1�D:\� ��T�K(3 E'!1*"& �DE�T1*(3#A�+��@ �"&�.rE �"��%#w@jDE(S�V(�D:�\DE"9c� 13�LD�'Gq�� ¤v¶>£}«d±Hªv¨#3=¤@§[§ � � � �����$/�#$���8���E��q

� ��d� ��@{�|Heq � � "9@ :(37� � q �!q � � :�*����r:� �*#2�0� �9q FNqL� ���w�13���3D:�\]�qL��<K(j�#�@$���� �3qL�N_o(3�*�*(* :��# #T� �\M�q Ä�¤@§T³ ¬ �.�bvD� �"9%���a :�*�9@A13�*��7@ :"&��(9#+%����� :(8Dv��"0�!"jr�yh#T�S;�*�T�!�* �P�RDE(&��(3�K'�# "$� ���A�7�jDE� ���3Sq ��³^§}��¤#²{��� � ���*�&U�Ul$�Ed��*q

� ���� ]���;# �A,zq ��B$�&@jDE��# #T(j�+f5q �+MN���3"9@(9# 13� ;�+[\q �+F�"�ED:�$y!qL�&��� �&�K(9����+_-qL�&<K��t�D:"0�$�A,zq �3q ÄJ¤@§^³ ¬ ��<K�7@ :"9� �"*D:�*1�DE�2"&�e(S%0(9�T�ED"9c{�T�&(8DE�/?�YEDv :�*�|P�'!�*EDE :"0%���*gjvDE E@1�Dp@ :�*��(31�DE�w?�LDv'V ��*#T(8DE�T"&�{x;0�w�kq���« ¬ � ® ³;£�¯³Rªv« ¬ ��� � /!&��%/�&��d$��d���UN�3q

� ��l� 4��*�T�K(9�����q _)qL�9y� E�!EDE �"&��%��Bkq _)qL�&_a(�D DE���!qLB�q �$_m(8DTDE"9c{���3q H�q*fN;���(*���#2��1*(�DE� "&�K"�r��"�7� Dv :"&�!���!� �R�2"&��Dv"&�!"&%� :(S��;�'DE"5D�;�YvD�@�&'K"&r{Dv;�I�"& :�K(3#+�!���EDv E@(9#1�'�13#2�jqB �¶>¯"¡�¤»¹º£�«d²{��� � ���������&Wl�X$X�� �j��d+q

� � � � ]��� ��V(S�$� �!q [bq ��B1�;$�V� �*D:�}Fbq �*qL�`4.@�P�w�"0tz� �!q 4hq � �5(*��(319�8(S@{�K_)q y!qL� ��(*��HV"& v�$� �3q �!q �}�b��"�R�LDE"�� � q ÄM¤@§�³ ¬ �_a"��9@#T(�DE� "&�-"&r>13"&%&��LD�� "9�{�E��A�819��r��T1a13"& �DE�T1*(3#5(31�DE�/?�LD�')P�')%+"&��(3�&(3#�ED��8 R"&� ��9gb(=�"���LDE �"&��E���!� �7� "&�aD�"&�!"&%� :(S��;�'ED�@�9'K�T�Kth"&�!���Gq#��£�«>ª ��³^§ ¬v� ª#³>² r ªv¨ � r�� ��� � /!$������ ���j�$����UN�3q

� ��X� � :�*���+�6�\4`q y!q��bvDE :"&%+���a(*��o13�� x�7P �(3#\P# "$"��mr:# "0teg�(C�!�*1*;�(*�+�/���D:"o��c��#T(3�/�~DE;���T�K�(31�D`"&r`�6EDv :"&%���)"9��Dp;{��T��13� �$���019��(S��YDv :��(8Dv�!���SD�"&r�y`#��S;�*�T�!�� x� I�&�/7��(j7�jq}½B¦^§#���¤v£H§l¨ ¬ ¼�«+¯�¤#¦>±J��¤#²�������������%+�&Wd����El�q

�TU�� B��!�LDv;$� �eq 4`q � �N@�P�T�RDE(j�&�9q �>q�<K�7@ :"&�T�K(9%�T��% "&ra(9%��T��% (*��� �6vDE :"&%+�����*rEr��*1�D:)"0��19���SDv :(3#^��8 �?"9@{��'ED��*���;�'R� "$# "&%�'Gq}�º¤v£#§l¨ ¬;r §l¤v£}¨ ¬ ���������&��0�3��$d��8�EX+q

�TUN� � Hh������� x7"&�� �!q ��q&�bEDE �"9%����A1*"&%��+� Dv� "&��+(*��K(`t`"&�V(9�� I :� ��u"&rNyh#T�S;�*�T�!�� �� ��&� 7�8(&��&q � ¯ ��� �v��¤#² �/���# � /!������� �����*BA� ��BGq

�TU�W � B��!�LDv;$� ��q 4hqL�&_a�w�"��;+�T�V(&�AB�qL���5@�;�# � �>q ��q � �N@�P�T�RDE(j���3q �Kq*�NrEr:��1�D:\"�r�# "0��%�TD:�� ���;+"j v�!"&��\DE;�� :(S��'K"&�V1S;"�# �w��� �%�T1�'���(*�&DE�T1Y1*"0�13���3DE �(8DE�T"&�\�w�K;��(3#LDE;$'h�"�EDv�!���"9�(S@{R(3#$th"&�!���Gq���¾ ¬ ¨l¦�i�¦>²R«>ªv£�¨t¦p« ¬ ��¤@§1³R´����.�����j�����3�+��l�X�� �9U{q

�TU�� � "& x��+�/��4hq y!q����kg�Bkq$].;�(jR�w��+H�q � (SP�*#T��T1*����3qAB$��T�*# �8 R�A4`qAB�t`�8 ��j#2"�rEr:�A��q9��(*�&%���*��*qL�d� ® ³R£�¯�³Rªv« ¬ «@Â�Á;Ä'´>¨[« ¬ «@ÂvÁ³>¦>²�ª ¬ ¨t¦R¨[ª#³ ¬ ³|¹>¹ ¬ ¨[ª#³$§l¨[«d¦>±�«»©�³>¦>²R£}«@Â$¤#¦>±3q�<K��t �}"j v��3���T# ��'A��MN� �*q�� � ���j���kqA�8d$X��E� ��q

�TU�U � 4��*R��� 1S���Bkq _)qL�K].�� :���&P(S@�!��B�qL� � "*D DE�*��V(S�$�}��qL�K]�"9@1S;�(3 :���}f�q��N(* �#w'�;�"& ��!"&��(3#��T��r:#w@A����13�3O"&��13"&%$�0�LD��T?�r�@���1�D:�2"&���T��%K�T�V19"&��%���+� Dv(3#+(3�& :����(3#$;�'&�A�8 v�#T(jR�T(q�'�¤#¥��T±»ÁJª ® « ¬ ��� ������$�$+���8X��8� ��q

�TUd� 4�"���� �3q M.q �|4�"&�*#LD�%���� �!qL�N[���@�2#�#T(S�$�|FbqL� �5@�;&��� x��HeqL�N,|@jDE# �� x� � q ]�q � �R �q ��R��"&r��*EDE �"&%���m�T�m'"9@�&%m%�T �#/zt`� Dv;fN@� v�0�� b�'$��& :"&�!��g&�*rEr��*1�D:\"9�K�!�*�!"& �'�q�� ¤v¶+£�« ¬ «@Â�Á{������������%���N���&U+�El��Aq

�TU�� 4�"������3q M.qL�&4�"&�*#LDE%+���$���!qL�+B&DE�8rE(S��(8DE"��� � q y!q �$[G�7@�T# #T(*��$FbqL���5@A�;���� x�0Heq �$]."&��9'�+,�q Ä^¤@§+³ ¬ �$y5��& :"&%+���$�� R�*��"&�7�T?�(j��+�81�D:\"&r�13"0%j�+� D�� "&�K�T�`%�T :# |th�LD�;KfN@+ E���8 \�'���& :"0�!�jq���¾ ¬ ¨l¦�i�¦>²R«>ªv£B¨l¦R« ¬ ��¤@§ ³R´����������������$WX&W�E�+q

�TUl� B"&�K�!�� x�\]�q�����g1�3q fYq �.q�4��T1�;�(3 ��0�"&��\�*�{qL��¾�«@Â;¦R¨»§1¨[«p¦Ê³>¦d² § ® ¤]¯�¤#¦>±v§l£�¶d³ ¬ ª3Á$ª ¬ ¤3�IB��� :�w��%�� x� �h�� :#T(9%�q �# � ��Ai ��"$#pqª ® ³|¹�§t¤v£�$�9���kq9��X��E���+q

�TU � � ��(* E?��T��$M�q [Nq*Hz@��V(S�V�/�SD��*#T# �T%���+13��g&R��c��&� rEr:�� R���019�6Sq � ª@§ ³ �/(¤#¦R¤@§ �H��¤#² � (¤v¯�¤ ¬[¬ « ¬ � �[£�«>¯³ � ��� �!����$�+��� �jX���W|���*q�TUX� ]����&PA"&th�k,zq F\q �|B3DE(*��# ��'���3qL,5qAB+��cC���Tr:r:�� :���+13�*5�T�u�K(8Dv;���K(8DE� 1*(9#� :��(jR"&�+�T��%u(*P�T# �LDv'Gg+�!"& x�`rE(31�D�*q r ªv¨[¤#¦Rªv¤3� � �����

$�$�$�|���&WX��E���3q

HA

L author manuscript inserm

-00243083, version 1

Å)À

� d��� ���T�`@ :(&� �!q�B�7c{�5��7c�@(9#�"& :� ���3DE(�DE� "9�-(*�+� 7��c�;"& :�!"0��6��T�rE#w@A���13�C;&@+�V(9�-19"&%����LD:�/?�mr�@��1�DE�2"&�Gqº¾�¶>£�£ y ¹T¨l¦� ¤v¶>£}«>´>¨[« ¬ ��� � �����&�&Wd�X��E�$�q

� d�� � Hh(3#w��� ��� �!q [\q�B�7c �&�Tr:r��8 R����13�*K�T�a�/�SD���# # �T%����19�jq��v�h�A# �T1*(8DE�T"&�`r�"j `�*�9@1*(8Dv� "&�Gq � ¯ �J�T±»Ásª ® « ¬ � � � � /!&� %�$�z�8��X��8��8�&WGq

� d&W � B�;�� Et`�T���]�q ]�q��5�*EDE :"0%���~(*�+�u13"&%$��LDE�T?�Kr�@+��1�D:� "0�eD�;� :"9@+%�;"9@jD\D�;�Kr:���K(&# �!#2��r��6x�(*�Gq��Q«d¥v³R£H§l¨t± �$��«>¶d¦>² � r Á$¯'¹ � ��������+��$/ ������ � �j�EX���q

� d��� B�;�� Et`�T���]�q ]�q9�bED� :"9%���K(*��`1*"&%��+� Dv�T?��r�@+�1�DE�2"&��w��%!�w�Kth"&�!���Gq}i�¦>²R«>ªv£�¡�¤#¥j�����������$�+���8�����Ed��6q� d&U � ,."&�`�jD�"&����3qL����(*�)yz�!�*#/�?"�"& �D:�.f5q ��_m@� v��;&'$� �!q|Hh4.f (*���)�LD:���r:r��81�D>"&�)��"& ��V(9#Y(S%�*�T��%�"jr�Dv;��P :(9�w� (S��

�����!���jD��T(q}U�£ �� �R¾ ¬ ¨l¦ �@� ® ³R£}¯³Rªv« ¬ �T�����.���j��%�$�$�&Ul��Ed��+q� d�d� � (*�&%&@A# � �A_-qL��4.(8DE1*#T�TrEr:� � qL�{H�@rEr:�A[\q �3q ��].�*# # �*��BkqL� ��(*��13��# ��_-q �3q ��[G� R1�;�� x��M�q Ä'¤@§u³ ¬ ���NrErE��1�D:5"&rb(9%�*��%������� x��(*���

�*�9@{1*(�DE�T"&� "9�a13"0%���LDE�T?�KD��6vD:K�T�a(� E@� :(9#.�8# �$�8 �#T'a13"&�K�K@+��LD�' R(9�`�# ��g��"& :�!KrE �"&��D�;��_O"&�"9��%�(9;�*#T( ��(9#�#2�*'������7�{���+�����3D��b# �$�8 R�B�@� E?���'Gq��Q¤v¶>£�«>¤»¹º¨l²R¤v¯�¨[« ¬ «@ÂvÁG���# � ��j�������$U�W�Ed0W{q

� d��� ].(3 E ��xD D��E,."&���+"j R�\��qL� �� :�LDE�3��B+�T#�?+�8 RED:�*�/�$� �>q � ����$�8 K�&� rEr��* :����13�*>�T� 19"&%����LD:�T?+�ur�@��1�DE�2"&�Ot��LDv; (S%��gADE;+�u4�(S�01S;"]��� E��(3 ���"�vD�@�9'Gq�� � � ¯ � (�¤v£�¨l³^§1£ � r «>ª������ � � �� 06���8d�X$�E�&UAq

� d�l� ,."9;������!qL�3���2#T�� �*��[\q3���Gg9_-q y!q����LD DE�T%�$y!qL,�q9FG�RDE�� x7���$�+�*��*qL� r ¤�6d�3£�¤ ¬ ³$§l¤#²�²R¨ ©[©p¤v£�¤#¦Rªv¤#±�¨l¦�ªv«@Â^¦R¨»§l¨l¥@¤>©d¶p¦Rª@§l¨[«d¦;¨l¦XÂ�q<K��t �K"& E��0yh1*(3�$���!� 15FG :�*�*q�� /!* 0�j���kqA��U+d��Ed�lAq

� d � � _a�LDE1�;�*#2#/����qwBkqL��� "j"$�07��<uq [bq$_a�T�&# �Tr:�5��"0�!���{� �(8D Dv :�wP�@jDE�T"&��(*P+"3@&DN�A�� :13�*�/?�*�>�!�*�!"& �'^1�;�(9��%�*9g"9P{7�� E?�(8DE�2"&�rE :"&��D�;�zB{��(8D2DE# ��_o� �&# �Tr:�\��"&�!���A� |HV��(3#LDv;eB&D�@�9'Gq���¼�«d¯�¤#¦E �¤#³ ¬ § ® (¤#¦>²�U�³d±H¤#²���¤#²A���������&�����&��$d��8�E�&WAq

� d�X� Hh������� x7"&�� �}q ��qL� � @jD�;� :� �*���3q 4`q � �5@+��# ��'�5��qL,�qL�5]\@+ E%��8 R��Heq � qL� �����$��8 REDE�*�T��5M�q.�bEDE �"&%������c��"��@ R�*u(S���!�*�!"& �'V(�D��V�2��#T� r:��g9(5�"9��@#T(�DE�T"&��2P(j7�*�VvD�@�9'!"&r�th"&�!���kq � ¤v¶>£�« ¬ «@ÂvÁG���������������j�|������X��El��3q

� ���� 4��*R��� 1S���Bkq _)q �\_o�xD Dv�8 R�\��q �6qL� �b"9������ ��V(9��|y!q ]�q��\EDE :"9%���a R�7�#T(319���!���jD�D�;+�8 �(*��'a(S��a#T"&��%+� Dp@{�&�T��(3#����*1*# �T�+�u�T�?� �@(9#+�!���!"j �'GqSy-�"�����PA# �I� :"*D��81�D��T?�5��rEr:�*1�D 51� ¤v¶+£�« ¬ «@Â�ÁG��� � /!&��������7UX��8�ElAq

� ��� � �b(*����� �zFbq FNqL��,\(3 �# R"9�$�z_-qL,zq �5F�#�(&���K(*��z]�q M�q ������# R;�E]."0;��!�* x� �!q y!q �z_m(*'+�8 R��M�q Bkq �KB3DE��rEr:����� �!qL,�q Ä ¤@§�³ ¬ �Hh"& ��!"&��C :�7�{#T(319���!���3D�DE;+�8 �(*��'O(*��O�T��13�2�����13�C"�r`yh#T�S;�*�T�!�� e�&� 7�8(&��C�T�-"&# ���� Kt`"&�!���kg�DE;+��,I(31�;�m,."9@+�SDv'BjD�@+�3'Gq��d³R¯³{���������0��$�����&W|��W���EXAq

� �&W � _a��'�� x��F\q _)q ��FG"9th�*#T# ��M�q H�q �\���T# R"&���4hqwBGqL����?��8 RR"&���45"���*�zBkq y!q � �5 :(S?�� Dv�3�.H�q _)qL��M�@&P"& xx�j'���3q M�q ÄE¤@§E³ ¬ ��y�"9��@#T(8Dv� "&��2P(j7�*��# "&��%�LD�@+���T��(3#KED�@�0'�"jr�13"&%&��LD��T?�ar�@+�1�DE�2"&���T��%��T�)D�;�O�!���+"3�+(*@{R(9#YDv :(*�R�LDE�2"&�Gq"�Q¤v¶>£�« ¬ «)ÂvÁG��������+���.��� �&���8�E�Aq

� ���� � (*�&�"0�$�$M�q;¼�«>¯�¤#¦�³+¦>² ³dÂ$¨1¦XÂ��J§l£B³d¦>±Hªv¤#¦+²R¨l¦XÂ]§ ® ¤¯9ÁJ§ ® ±jg8<}��t �h"& ��&� � � Gq� �&U � B�;�� Et`�T��5]�q ]�q.�bEDE �"9%���-(*�+� E"& �(*���& :"&%���� :�7�A#�(913���!����DhDp;�8 �(*��'�(*���-1*"0%���LDE�T?�or�@��1�D�� "9��T��%��T� �@ v%0�21*(3#T#T'

�!���"&�(S@{R(9#�t�"&�!���kq}�T±»ÁJª ® «d¦R¤v¶>£�«+¤#¦>²R«>ªv£�¨t¦R« ¬ «@Â�ÁG��� �������� ����0Ud��Ed�l+q� ��d� <K(*�$�� �+4�q ��q ��B�w��r:"& :�T(*�+�/�+��q �+_m(S@� :� �+_-q �+]."3�+"0� � q �+F�"&#�(�DTDE� �+[bq �&<`(S���� � � q9_a���!"& E'!r�@+��1�D:� "0�0�/��%!(8D��!���"&�(S@{R��g

�T�`�(31�D�"&r�(*%�5�w�!"&?�(3 ��T�*1�DE"&�!� �9�*�`th"&�!���Gq.(PÁ;¦R¤@ªv« ¬Jy ´d±�§1¤@§)½B¦>¥@¤#±�§ ��� � � 0�*106�&WX$�E���Aq� ���� _m@{�1*(* :�+MN�T�����q �0yh�T�+�T����3q M�qL� � "&"�����]�qL,zq3F� :���K(8D�@ ����!�*�"9�(S@{R�5(3r DE�� N1*(S�13�� GDE ��8(�DE�!���3D�qd¾T³>¦;ªv¤v£9��£B³Rª@§ ��� � � �

06�|����U��WN�*q� ��l� ��?�(*��� �!q y!q&�bEDv�T�V(�DE�*�`� ���?0(9# ���19��"&rNyh#T�S;�*�T�!�� x� ��&� ���(�R���w�hDE;+� �5��LD��*��BjDE(�DE�**qB��¨ ¬ ´d³>¦�+ � � � ��� � ���������+W��l$�

�jXAq� � � � 4��LDE1�;�2�6� �!qL� ��� #2���8(&� �!q$�:5R���� # �`���������SD��T( �:(9%�*�� x�*#T(�DE�*� ��"& �:(S%�*�T��%�� R�*#T(8DE�*� ��58�:�E��?+� ������13�`rE :"&� �!��Dv(j��(*��(9#T'R�

"&rN�����!���jDE�T(5�+ :�7?0(&# ����19�Y�/��D�;+��"�# �$�6ED�"$# �Aq�3.³>¦Rªv¤@§ ���# � ���� ���&�X&���8��U�q� ��X� �.D D:�Iy!qL��]. :�RDE�*# �� x��_-q _)q � ��(*�OHh(9 x���(S�h�{��[\q ��,.#T(*@Ax���*q �3q � ��(*� �`�8 �,.(S�K�!���$��f5q �6qL� � :"9P�P�*�*� �!q ��q Ä�¤@§�³ ¬ �

FG ���?�(3#2���13�m"�r}yh#T�*;�*�/�!�* x� ���� ���(j7�m(*���«?�(jR1�@#T(9 e�&�������SD��T(g.(&�R"&1*�T(8DE�2"&�-t��LDv; �*�9@1*(�DE� "&�Gq.f|;��m4�"*D D��8 ��j(9�ED�@�9'Gq}U�¯��j��� � ����� �������X�l$���EX��+q

� l��� y������ x7���� �!qL�+MN(S@����8 R�AM�q �3q � ����th��'�A_�q ��q ��MN�xDv������7@ x�+M�qL� �bD2D:�$y!q �A,I"9�{��#T(3�������9q 4`q Ä�¤@§$³ ¬ � � ������� .���TrEr:�� x����19�3�T�hDv;���T��13�2�����13�z"�rNy���(*�+�K?�(jR1�@+#�(9 b�$���e���3D:�T(+g�f|;��� �54 � ���|_�B&D�@��� �**q&� �54 � ���|_ �v�019� �����19�54Y�*7�8(9 :1�;� :"9@���q��Q¤v¶>£�« ¬ «@ÂvÁG� � � � ���%/ &�N�8X&X&W+�ElAq

� l�� � ��(3�$�6� �3q F\q �\_a�T RR����\f5q 4`q �|Hh(91�;0�/�$x�� ���!qL,�qL�N[�� ��V(9��\_-qL�\M�(*@�.,5qL�\_a�� xx�0��'�|Heq�f|;��13#T�T�+��1*(9#����T(S%��"��� >"&ryh#T�*;�*�/�!�8 �� \��� 7�8(&R�&q � £}ª ® ��Q¤v¶>£�« ¬ �T��� �*!$����&W$U�EXAq

� l&W � � (3"��`B�q ��H`����& :� �*��HeqL,�qL��H`(3#T# � �!qwBkq ��H�@� �`B�qbf|;��a ��*# (8DE�T"&��;+���A�PA�xDvth�*����(*%�*��7��c{�5(S�0�OD�;�O�T��19� ������13�O"&r�����!���jD��T(�(*���zyh#T�*;�*�T�!�� \��� ���(jR��g9(5�!�RDE(j��(S��(3#T'R� *q � £�ª ® (¤#¦��T±»Á$ª ® ¨l³^§l£[ÁG��� � �0��%�%�� �j�$X����8dAq

� l��� �N��#T(*�+�0�}Bkq �KqL�54�"&1*1*(&����q y!qL�5FG�RDE�� x7�����4`q ,�q ��,\;�(&�54hq HeqL����"9���!����z��q �����!���jDE�T()(S�0��y`#��S;�*�T�!�� ~�$�/7��(jR��T��13� �$���019�� �(8DE�*\��"z�"*D�?0(9 E'`P�'!��7c!�T�K4�"&1*;�*ED��8 R��_o�w���Gq � £�ª ® �Q¤v¶>£�« ¬ �����������%��+���8d �jX$�EX��+q

� l&U � _a"& : �� ����*qL,5qL�$Hh��'��K(3��{y}qL��_a"9;��A4`q ,5qL�$H�@$%j;+�6����3q Fbq �+?�(*��]��*#T# �*� � qL�A[��T#�#2���jP+(*@+�}� � q Ä'¤@§u³ ¬ �AfN;��h,I"&��"& �DE�w@�DE"��bvDE(*P#T� �;�(�4���%� EDE v'�r:"& oyh#T�*;+�*�T�!�* x� �`�/7��(jR���E,.�N4Iy �z��qKFG(9 Da��q!,I#T���+��1*(9#~(S�� ���@+ :"9�{�'01S;"�# "0%0�21*(3#(j���6���!���3D�"&r�yh#T�*;�*�/�!�8 R� .�&� ���(j7�&q��Q¤v¶>£�« ¬ «)ÂvÁG��� ��� 0�� #��|���8d&X��E��dAq

� l�d� ]\@1*�$t�(9#LD:�� x���9q � qL�zB"9P�*# �5��qL� ��@��&�$��_-q ��q � ���T�3�5_)q _-q �YHh������� xR"0�$� �}q ��q � ������� u�&� rEr:�� R����13�*C"&�-(oP :�T��r�!�8(&�@ R��"&r�13"0%���LDE�T?��r�@��1�D�� "9��T��%K�T��yh#T�*;�*�T�!�� �� \��� 7�8(&R�jq � £�ª ® ��Q¤v¶>£�« ¬ ����� � ��0�*%/����l�d$l��E���+q

� l��� Hh������� x7"&����!q ��qL�`]\@1*��t�(9# D��� x���3q � q�,I"3%$��LDE�T?������r:�T13��D�m"&ru�!����(9���th"0�!����t`� Dv;�y`#��S;�*�T�!�* R� o��� ���(jR�&q� ¤v¶>£}« ¬ «@ÂvÁ � � ���*���X��$�E�Aq

HA

L author manuscript inserm

-00243083, version 1

Å �

� l�l� 4��w��T1*;� �!q <uqL�AFG�RDE ���#2#/��Bkq y!qL����;�LD���;"9@{7�6��Fbq �3qL� �b�T"&# �A��q ��q � ���+���8 ����Tr:r��8 ����13�*5�T�u#T(*��%&@(S%�K"&r.y����(8Dv� ���3D:3g$(# "&�&%�LD�@A�&�T��(3#AED�@�&'Gq�� ¤v¶>£}« ¬ «@ÂvÁG� � � ���*�%���WX$X��E���&WAq

� l � � ].(*'#2�6�� �!q y}qL�>y���@+�V(&��f5q ��,I E@�*��4�q [NqL�!f\"9�!"��*�&(j�u,zq �!q �K� "�"����&�3q y!qL��_a"9�3DE%+"&�!�8 �'����q ]�qL�&�R 8q � ���+���8 ���TrEr:�� R���019�3>�T� #T(*�$%j@+(*%�C"&r`y�#2�*;�*�T�!�� K��� 7�8(&��>�(�DE� ���3D:> :��?� R�LD��*�Aq ��¬0­#® ¤v¨µ¯�¤v£�'�¨l± � ±�±H«>ª '�¨l±H«>£B²A��� � � ���� ���8� �j��U+�Aq

� l�X� y� E�A�8# ����3qL,�q�f|;��hr����V(&# ��P :(9����;�'&�"��3EDE �"9%���� 1`13"&�3D��T�&@�@+��rE �"&� Dv;�z� :���!���AEDE E@+(3#kx'���& :"&�!��DE"��!���+"&�(*@AR�jqy-;$'j�A"*DE;+�67� \(*���h ���?� ��t�"&rN�@����+"j �DE�T�&%!�&(8DE(+q � �v¡�¤»¹º£�«d² �B��¤#² � ��� � ��������������$�E��X+q

���j�� FG��(3 �#/vDE�*�T��\f�qL�N4�"�R���� �!qL��BjDE"9��*�|y!q ]�q�_o"�"��o��� R"& x�$�8 RK(*���=�!���"9�(*@{7�&q;i�¦>²R«>ªv£}¨l¦R« ¬ �$� ¤@§1³R´ ��¾ ¬ ¨l¦ �1� «+£|§ ® �� ¯ � ��� � /!���$��3�$Wl�X��EX0U{q

���G� � � :�w%"& ���(9��� ���Bkq � ��������*�&'��Bkq H!q*4�"&# �5"&rN�*EDE �"3%+���!�T��Dp;�bDE ��8(�D��!���3DN"&r������ ��6�7�T"&�Gq � ¯ ��¢ ® ¤v£8����������������d$�����EXAq���3W � 4�"&�3���&PA�8 v%��BkqL��[��8#2# ���V(9���A,zq � �5 :"&# # �+_-qL� ��(*���& x"0�K�!�3���3q3f|;��5�!���"9�(S@{��5�T�!��@ :"9�A�jq#½B¦^§ ��� �d�º¤v£#§l¨ ¬ �9¼�«>¯�¤#¦+± �

��¤#² � ������������%+��� �3W�EX+q���j�� ��# "�"�ED��� EP"��� x��Heq �3q ���N�$�8 v?�*����zy}q � q�FG �"�C(*���13"&�="�ru�7c{� EDE�/��% Dv :��(8Dv�!���SD^�!"��&(&# �LDE� �*m�T��"�ED��*"9�{"& :"�7� *g5(

1*"&�K�(9 :� R"&�CP{�RDvth�*���^D��wP{"&# "0��6�IB�|4�_ `(S���m�6EDv :"&%���a� � p�2� �"3%+�6ED�"&%�����.DE ��8(�DE�!���3D:*q�� r §l¤v£�«+¨l²]U�¨[«>ª ® ¤v¯ ��« ¬U�¨[« ¬ �������������/ &�N��d�l$�E��dAq

���3U � �b�*13�A4`q [Nq �+f| :�w?�*��� �A_�q y}q$�NrEr:�*1�D��"$r\;"& :�!"0��� R���+#�(913�������SD�Dv;�� :(*�$'^"0�e13"0%���LDE�T?�`(*%+�T�&%^(S��������!���jD��T(K :� ��u�T��"�EDv�!���"9�(*@{�(3#�th"0�!���kgG(� ���?�2��t�"&r5"&��%"$�T�&%�#T(3 v%�*�ER13(9#��*��# "0��%�TD:�� �� 13#2�T��T1*(3#GDv :�T(3# *qJ¾ ¬ ¨[¯³;ª@§l¤v£�¨[ª*�1�������0� %���W�W�E�0UGq

���jd� [G�T# �*�.B�q ��q ��Hh��(3 :��� �3q �.q ��4.'&�!�8 R�"�9qAfb �"9@�%&;a"��6vDE :(9�j�2"�#b#2�*?�*# `(j7R"&13�T(8DE�*�Ct`� Dp;�19"&%���LDE�T?+�e�/�K�(3�T ��!���3D5�T�~�A"�ED:��!���"&�(S@{R(9#Ath"&�!����(3r D��8 K���K'+�8(9 x�"&rb"��*EDE �(3�&� "�#��T�K�#T(9�jD:*q��T±»Á$ª ® « ¹ ® ³R£�¯³Rªv« ¬ «@ÂvÁ � U�¤v£ ¬ � ���������������.�&�.�8�$l�����WAq����@�P!W+���&W`[G�7P!WN�3q

���j�� FA;�� # #T�w�{��IBkq _�q �\B$;�8 vth�T��|]�q ]�q��NrEr��81�D:`"$r��6vDE :"&%+���a"&�~�!�S�!"& :'mr�@+�01�Dv� "&�a�T�a�@ v%0�21*(3# #w'm�!���"&�+(*@{R(9#Nt`"&�!���kq�T±»ÁJª ® «p¦R¤v¶>£�«>¤#¦+²R«>ªv£�¨l¦;« ¬ «@ÂvÁG��� � ��0����06�&U �&d��EX�d+q

���jl� �5@���(j�+f5q �$f\(j����� x�+4hq �+_a1�%"0t�(S����3q [bq9fN;�z�*rEr:�*1�D:�"&rb���pth�*���u�6EDv :"&%����;"& v�!"&��� R�7�#T(313���!���&Db"0�e13"0%���� D�� "&���T��*# ���� :#T'�;��(3#LDE;$'Vr����V(&# �**q}�=±<Á$ª ® « ¹ ® ³;£�¯³Rªv« ¬ «@ÂvÁ�� �[´>¤v£ ¬ � �.����������*������W+X��E��XAq

��� � � MN�7P{#T(*�+13�`��qwBGq � ��(S�0"9th���'���3qL�h,Z;0(S��`]�q �>q �5<}�8# 7"3��zHuq �!q�Hh"& E�!"&�+� ����A#T(319���!���jD!D�;+�8 �(*��'�(S���13"&%&��LD�� "9�kg�'ED����V(�DE�T1Y ���?� ��t�(*����!�RDE(j��(S��(3#T'R� *q��d³R¯³{���������S��$���%���7U �jX��EX�X�q

���jX� Hh"&%�� E?+"j RED:����qL���`(3rEr��6� �!qL�A4��T1S;0(9 :�����_-qL�+H�@$����� �D:��[Nq&Hh"& ��!"&��` :�7�{#T(913���!���3DNDv;�8 �(*��'�r:"& .13"0%���� D��T?�`r�@+�01�D��T"&��T�`�"�EDE�!���+"3�+(*@{R(9#Kt�"&�!���kqd¾�«+ª ® £B³>¦R¤��#'�³R§1³R´p³>±H¤�� r Á;±v§ �#¡�¤#¥ � ������������,��h�$�����*q

� X��� _a(S�0� �5F\qL��Hh"9%�� E?"& xvD:�5��q\f|;�m�!���"0�(*@{��m(*��«Hh4�f5q|Hh4�f¡(*����13"&%&��LD��T?�o���*1*# �T��&q�U�¤#±v§��º£|³Rª@§�¡�¤#± ¾ ¬ ¨l¦i�¦>²R«+ªv£�¨l¦R« ¬ � ¤@§1³R´��������������08�|�8��d���W�WAq

� X�� � 4��T13�*���!qL��_o"j RR�*�,zq3_o�8(&�@ :�w�&%!13"9%��+� D�� "9�!�T�K�!���"0�(*@{��Y ��67��(3 :1�;Gg9(� :��?+� ��t�"&rAD:�*ED�@{7�&qX¾ ¬ ¨[¯³Rª@§t¤v£�¨[ª3�������������j�W��W�WGq

� X&W � ].(3 E ��xD D��E,."&���+"j R�5��q � �5 :�LDE�3��B�T#T?+�8 RED:���T�� �!qI�bEDE �"3%+���- :���#T(913���!���3DhDv;�� :(S��'-(*����13"9%���LD��w?�ar�@+��1�DE� "&���T�-"�#2���8 th"&�!���Gq��d³R¯³{��� � ��+��$����0W����l���U|�6q

� X��� FG"&# "�����(9�3DE"�#T(j�$Fbq ��F�"& DE�w�$�$4hqL�&F�"&# "����KqL�0Hh��# ����w@{��0HeqL���E �R(*#�(&� �>q �$�N E�&��"�#T(j�$4hq*f|;��5�8r�r:��1�DN"&rNR;"& �D:�TDE�� :���*EDE �"&%��� :�7�#T(319���!���jDGDv;�� :(*�$'e"&��13"9%���LD���"0�kg�(` :(S�0�$"&�!�T�3�*���A��"9@�PA# �*�2P{#2�T����+1* :"����v"&?�� kDv :�T(3#����>�{"�EDv�!���"9�(S@{R(3#�th"&�!���Gqy ´d±�§t¤@§�(�Á;¦R¤vªv« ¬ ��� � ���*�/���&Ud$X��E���+q

� X&U � ,.(* �#/�"&��KM�q ��q ��B�;��� Eth�/�$�}]�q ]�qKBjDv�8 �"j�2��;+"j ��!"&�+�6��}�!���!"& �'�(S����!"�"����w��(�;��(&# Dp;�'��*# ���� x#w'��{"9��@A#T(8DE�T"&�Gq�T±»ÁJª ® «p¦R¤v¶>£�«>¤#¦+²R«>ªv£�¨l¦;« ¬ «@ÂvÁG��� � �0�*$/ ���d �&���E�����+q

� X�d� ���T�`@ :(&� �!q.�\ED� :"9%���- R�7�#T(313���!���&DhDv;�� :(*�$'-�K(9')� :"*D��*1�D!(S%�(3�w�ED��T�3D:��# # �*1�Dp@(3#`����13# �T�+�a�T� �{"�EDv�!���"9�(S@{R(3#th"&�!���GqB �«>£�¯ �)U�¤ ® ³+¥ �/� � � ���*$�������7W��WN�*q

� X��� �� :(S���6����q ]�qL��Hh���+���8 RR"&�� �}q ��qL�=BjD�(*��1*�S'���u[\q �5q ��_m1*1*# �8(9 E'�C,�q y!q ��]. :"0tY��>��qwBkqL�CB$�!� Dp;$�C,�q y!q Ä�¤@§Í³ ¬ �yh��"&19��(�DE�T"&� P{�RDEt`�*��� 19�T :1�@#T(8Dv�T��% 7�7c vD:�� :"��2��;+"j v�!"&��*�(*��s1*"&%��+� Dv� "&���T� �+"j ��K(3#O�*# ���� :#/'�t`"&�!���kq� ¤v¶>£}« ¬ «@ÂvÁG�*����������%���d�X&X��E�$���Aq

� X�l� MN�T���*�K(9'�� x�$M�qL�+B���!#T�LD:R1S;$�0Heq �!qL�AB+(3#T�xDp@{��]�qL�$]."&1��$� � qL��B�(3#T�xDp@{�E�S'j;+#�(9 :�3� � q � �b"9%�;#T(9�K�/�$y!q Ä$¤@§+³ ¬ ����"9@�P+# �6�2PA# �T������#T(319��P"+��13"&�3DE �"�#T# �*���{�'�1*;"&�!��Dv :�T1eEDp@��� �*�"0�eD�;�>�*rEr:�*1�D:z"&r�(�1*"&�`P�T�+�*�~�*EDE �"&%���{�2� �"&%�*EDE�T�C :��%�T�!���C?�� x�@A�6vDE :"&%+��� (3# "&�+� "0� �{�� :rE"& ��V(S�13�*� �!"�"�� (S�� ��� x�"&��(3# �LDv' "jr �!���"9�(S@{R(3#��'���& :"&�!� �(�DE� ���3D:*q� £ ­ ¦;¤v¨[¯�¨»§[§t¤ ¬ ©d«d£B±Hª ® ¶p¦XÂG���������3��%/�&�&W+� �j��UdAq

� X � � 4��*R��� 1S���Bkq _)qL�+_a(S���/��Fbq _-q��|rErE�81�D:�"jr\;+"j ��K"&��` :�7�{#T(913���!���jD�D�;�� :(S��'u"&�e19"&%���LDE�/?��(9���KP �(3�T��(*%�w��%Gq � ¦>¦ ��� �� � � ª#³>² � r ªv¨ �����������j�������&W���$����UAq

� X�X� fb"& �(*���(3#T# �� :(S�0���+,�q �!q*�\ED� :"9%���K(j\(.D� :��(8D��!���3D�r:"& �y�# ��;+�*� �!�� b�&� 7�8(&��&q��d³;¯³ ����������$���������l$� �q�R�8���� 4�(S�����Bkq 4`q ���b����#T(*����A_�q y}qL��B�;&@��K(3�+�8 R��BGq y!q �{Hh�7����� x7"&�� �!q ��qL�A]. E@$�j�+�8 R�A4hq M.qL�+_a(S�$�"3����3q ��q ÄJ¤@§$³ ¬ ���NrErE��1�D

"&r��3EDE �"3%+���m�{#w@{z� �"&%�*EDE�T�a"0�m%# "9P(3#.1*"0%���LDE�T?��r�@+��1�D:� "0�a�T�~�A"�EDv�!���"9�(*@{�(3#\th"&�!����gDv;�K��"0�!���{� zHK�8(&#LD�;����LDE�T(8DE�/?��_O���!"& �'eB&D�@�9'kg9(Y �(*���&"&�!� �9�*�h19"&�3DE :"�#T# �*�5DE ���(9#Eq��d³R¯�³{�����������$������$W���&���El&W�q

�R�8��� � �� :�LDE�/��% � �"9@���r:"& uD�;+� ��"&�!���{� =HK�8(&#LD�;��E�+� Dv��(�DE�T?���E�$?�6vDE�T%�(8DE"& R*q�4��/x�$ (*�� P{����*r��LD:o"�rm�6vDE :"&%+�����+#�@A� :"9%�*ED��T�K�T�h;+�8(9# Dv;�'`�"�EDv�!���"&�(S@{R(3#$t�"&�!���kq��d³R¯³{�����������$�������0WN�8�E���Aq

HA

L author manuscript inserm

-00243083, version 1

Å)¿

�R�8�&W � y������ x�"&�� � q M�q �IMN�T�K(31�;�� x��_�q �Iyh�R(3r:�Zy!q 4`q ��].(j7RrE"& E�0��f�qL�I].�8 R�*Rr:"& :���zBkq y!qL��].#�(91���.H�q Ĥ@§�³ ¬ ���|rErE�*1�D:�"&r1*"&� ��@+%0(�DE�*�C� �3@A�T��>�6vDE :"&%+�����T���{"�EDv�!���"9�(*@AR(3#�t`"&�!�*�Cth�LD�;C;�'ED:�� R�81�D�"&�K'kg$DE;����"&�!���{� 5HK�8(&#LD�;~�v��LD:�T(�DE�w?{� :(S�0�&"&�!�2�3�*�`13"&�3DE �"�#T# �*�YDv :�T(3#Eq��d³R¯³{������������$��/�����8l$���8����WAq

�R�8���� �b���*#T(S����A_-q y!qL�A4.(S���{��BGq 4�qL��B�;&@�K(*�+�8 R��Bkq y!qL�A]\ E@��&��� x��4hq �A_m(*�R"0�$���3q ��q ��B�;��� Eth�T���]�q ]�q Ä�¤@§$³ ¬ �G,."9� ��@�%�(8D��*�� �9@{�T�+� �*EDE �"&%���C(*�+��%0#2"3P+(3#`13"&%��+� Dv�T?�Or�@��1�DE�2"&���w�-�A"�EDE�!���+"3�+(*@{R(9#�t`"&�!���kg.��"&�!���{� �HK�8(9#LDE;��E���LD:�T(�DE�w?{�_a���!"& �'eB&D�@�9'Gq��d³;¯³{������������$��/�&�&WX�d$X��E� �q

�R�8�&U � y��K(j�9@191*� �NM�q y!qL�N[A �(�DE�w%# �T"&�� �|M�qL��4�"&1*1*(&�G��q y!qL��[G�T�*�1�;+���b,5qL��M|��?� R��(j��F\q �|FG����"&��*� �>q Ä�¤@§P³ ¬ �N4��/x��rE(91�DE"& x`rE"& 1*# �T��� 1*(9# #T'~�&�T(9%���"07�*��yh#T�*;�*�T�!�� x� ���� 7�8(&��&gA(>1*(jR�*�E19"3�3DE �"�#)ED�@�0'~"�r.(*�C� DE(3#T�T(*�u�+"3�$@{#T(8Dv� "&�Gq#� ¤v¶>£�« ¬ «@ÂvÁG� � �� �0� ��j�+X&W&W�E���3q

�R�8��d� Hh��'��K(9�$�zy!qL����� #T��/�$�"&�����q ��qL�}BjDE(9rErE"& :���)�9q y!qL��Hh�*#T�^7��_�q �*qL�`B+��%$�!"&��zy}q HeqL�����*�/�jPA�� E%��f5qIyh#T�*;�*�T�!�� x� ��� ���(j���g3(hvD�@�9'V"&rN�7�A� �����!� "�#2"&%�T1*(3#+(j��+�81�D:Sq � ¦+¦ �,� ¤v¶+£�« ¬ � ��� ��������#%������d$��UN�3q

�R�8���� � :(S?��6��ky}q ]�qL�+��;�LD��6����qL� ��"��7�{7�*# # �Gf5q �!q ��4��8� rE#2�8 R�G]�q �}qw� ��(S�~]��*# #2�6� � qL��MN(3 RR"9��G��q ]�q Ä9¤@§s³ ¬ �Gy¡1*(jR�3��19"&�3DE :"&#ED�@�9'!"&r�yh# ��;�*�/�e�� x� \��� 7�8(&��&q � ¦>¦ �,�Q¤v¶>£�« ¬ � ��� � �����$����l&���$�El&UGq

�R�8��l� ]. :�����+�8 R� �!q ��q � �5@��&@#2#/�z��q y!q �^BjDE�� E%�(91�;� ��`y!qL� ��(*��]��*#�#2�6� � qL�K]�"0th���� �3q �!qL�`_a1*1*"& ��!�T1*���� q ,zq Ä�¤@§�³ ¬ �FG"�EDv�!���"9�(*@AR(3#5�*EDE :"9%���) ����A#T(313���!���&DYDv;�� :(S��' (S��~Dv;�C :� ��-"&r`yh#T�*;+�*�T�!�* x� ¥��� 7�8(&��&g\(C�"9��@A#�(�DE� "9�{�2P(&R�*�1*(jR�*��13"0�SDv :"�#AED�@�0'�q � ¯ �#� �@i^¹.¨l²;¤v¯�¨[« ¬ �T��� � ������/�&�$W�&W�El+q

�R�8� � � B�*R;�(9�j �� ��BkqL� �b"& E�&P�� E%� � q M�qL� ���8 vP�'�KM�q ��q �K_='0�� x7�`_-q ��q � ���T1���`HeqL� �z E(31�;��K(*�� �>q y!qzFG"�EDv�!���"9�(*@{�(3#�6vDE :"&%+���V ����A#T(313���!���&DAD�;�� :(*�$'V(S�0�5D�;�� :� ��V"&r�yh#T�S;�*�T�!�� b�&� ���(j7�&q � £}ª ® � ¤v¶>£�« ¬ �*�������j�*%�����U�&d���U+�Aq

�R�8��X� FG(S%0(S���T�����2Hh� # # �{y}qL�$HK���+���8 R�"0�$� �!q � q&�bEDE �"3%+���e���*r���19� ����1*'!(9���! ��/��e"&r\y�# �S;�*�T�!�� x� ���� 7�8(&����/�!th"&�!���Gq � ¯ ��� �i^¹T¨l²;¤v¯�¨[« ¬ �T���# . ������/�&�$Wd����E���6q

�R���8�� ]. :"��*� � q y!qL��Hh����$�8 RR"&���y!qwBkqL�N,\ :��(j���'$�kHeqL�G_o13,\@{x�0�� x����qL���z"j �DE�����y!q ��qL�1��"& E�!��y!q [bq Ä=¤@§s³ ¬ �Gy¡1*(jR�*�E1*"&�3DE �"�#ED�@�9'!"&r�yh# ��;�*�/�e�� x� \��� 7�8(&����T�`yY@AEDE :(9#T��(+q��Q¤v¶>£�« ¬ «@Â�ÁG���, � ����������8��X �j�El���lAq

�R����� � Hh������� x7"&�� �!q ��qL��FG(S%�(*���T�� ��;+��#2#/��y!qL���N�K(*�&@A�*# �N,�q �!qL� �5@������_�q ��qL��]\@1���t�(3#LD��8 R�1�3q � qA�\ED� :"9%���~ R�7�#T(313���!���&DD�;�� :(S��'��T��"$# ���� uth"0�!���kq�,."&�K�+(3 :� R"0�$�P{�RDvth�*��� y`# ��;�*�T�!�* R� o�j� 7�8(&��O1*(&��*m(S����"0������!���jD��*��13"&�3DE �"�#�@�P �7�81�D:Sq � £}ª ® �,� ¤v¶+£�« ¬ � ��� � �����%/�&� �jX��$�EX����Aq

�R����W � ��(3 ��w�j%��B�q ,zqL�N4�"j1*1*(&����q y!q �\F��xD��� xR����\4hqL,zq ����� P+ :�T����.FbqL,5q �\fN(*�&%�(3# "���\��q � q � �z"3�$�!���$�I��q�FG"�EDv�!���"9�(S@{R(3#�6vDE :"&%+���V ����A#T(313���!���&DAD�;�� :(*�$'V(S�0�` :� ��!"&r�y��!g9(��"9��@#T(�DE�T"&�{�2P(&R�*�VvD�@�&'Gq�� ¤v¶>£�« ¬ «@ÂvÁA���# � � ���%�$�$X���d��El���q

�R���8�� _a"& �Dv�*#/� �>q [\q �+_o��'�8 R���3qwBGq&MN(31��!"$r��{"�EDv�!���"9�(S@{R(3#��6vDE :"&%+���! x�7�A#�(913���!���3D�D�;�� :(S��'!(9�0�`D�;�� �� R��"jr«�����!���jDE�T(q� ��Q¤v¶>£�« ¹=±»Á$ª ® ¨l³^§1£[Á��;¾ ¬ ¨l¦ �,�Q¤v¶>£�«d±#ªv¨ � ���# � ����108�+���9U�ElAq

�R����U � B#T"�"*D��8 R�+y!q �3qL�A]. :"9��*"0?0(&���3qL�$���LD DE���K(3����3qL,�qL� ��(*��]. :"��*1S��;"&?+���$��,�qL�+H`"jrv�V(S��Ay!qL�+?�(9� ��@{� �R��G,zq _-q��\ED� :"9%���@{R�`(*����8(9 :#T'~"0�$7�RD.y�# �S;�*�T�!�� x� z��� ���(j���g(}�"9��@A#�(�DE�T"&�{�pP(jR���uED�@A�&'Gq#� � ¤v¶>£�« ¬ � ¤v¶>£}«d±H¶>£5Â��=±<Á$ª ® ¨l³^§l£µÁG�"�# � � ����06�+l�l&X�� �G�3q

�R���8d� MN�� :�+�8 R�`y!qL� ��"����}��q � ���7P(*���+�6�^BkqL�K4�"3t�#T(9���� �!qL�>B&�K'3Dv;$� �!qL�K[A ����*�$#�(S����K4`qKB��!"0�0�/��%�(S���"��6vDE :"&%+���{� :�7�#T(319���!���jDAD�;�� :(S��'V(&|�� :"*DE��1�D:�T?+��rE(31�Dv"j R\rE"& �y�# �*;�*�/�!�8 �� \�&� ���(j7�&q�3.³>¦Rªv¤@§ ���# � /!��� *�����U�������U�q

�R���8�� ].(3# �$�8 ��671*;�� ��_-qL� �z�~,.(9 :#T"���y!qL��MN�7�{"& R�*���!q �^]. :(31*1*"+��M�qL��_m(*%&%� �CB�qL� � :�w%"�# �RD DE"���[\q ÄS¤@§�³ ¬ �u�bED� �"3%+���{� :�7�#T(319���!���jDAD�;�� :(S��'V(S��`yh#T�*;+�*�T�!�8 R� .�$�/7��(jR�5�T��D�;��� DE(3# �T(S��MN"&�$%�LD�@���T��(9#GB&D�@�&'!"9�Ky�%�/��%Gq��Q¤v¶>£�« ¬ «)ÂvÁG���, � ��%/���+X�X&�����8���0WGq

�R���8l� fN(*�&%�+_-q �eqL����(91*"9P{�� �!qL��BjDE�� E�����qL�+_a(* ��&�8 R� �!qL��B1�;"&r:�2�*# ���+FbqL� � @ �#�(S���0�+]�q ÄJ¤@§^³ ¬ �A�NrEr��81�D\"&r."��*EDE :"0%���e�9@ ��T��%�!���"&�(S@{R�5"9�V �� R�K(*���`(*%��(8D�"9���RD�"�r�y�#2�*;�*�T�!�� x� \��� ���(j7�jq�39³+¦Rªv¤@§ ��� � ���� ���0�$U&WX��E�&W�q

�R��� � � ��(*t�(&��G,zq ��4��*���� 1*��|Bkq ��_a"& E :� R"&���y!qL�G]. �"&"&���!��'�* R�G4`q ��,."& E �(3�&(3��_)q � �b"9����� ��V(9���y}q Ä9¤@§s³ ¬ ��y�� :"���+�81�D��T?�ED�@�9'�"&r!�*EDE :"0%���- :�7�A#�(913���!���jDzDE;�� :(S��')(*��oD�;�m :� ��-"&r ����?�*# "9�A�T��%)yh#T�S;�*�T�!�� �� u�&� ���(j7��g�DE;+�m].(3#LD:�/�!"j R�MN"&��%��LD�@A���T��(3#�BjDp@�9'!"jr�y�%+�T��%Gq��Q¤v¶>£�« ¬ «@ÂvÁG��� � /!&��������d���l���WN�3q

�R���8X� �`(3rEr:�*� �!qL�\B+(*t�(*'�(&� � q ��MN�T��PA�8 vP�@ v%$����q � � E(9�9'$� �!qA�bEDv E"&%���eDv;�� :(*�$'~�T�u�A"�EDE�!���+"3�+(*@{R(9#�th"&�!����g��*rEr:��1�D:`"&�1*"&%���LDE�/?��r�@+��1�D:� "0��(*���`�����!���jD��T(q��d³R¯³{���# � �����$ 0 ����� � �3�EX�dAq

�R��W�� Hh"&%�� E?+"j RED:����qL�+���T#T# �T(3�!����3qL��]\@�&%�*��_-qL��4��T�*���*# �+��qL����"�#T# �3����3q+f|;0�`��(�D�@ :�K"&rNDv;�K�*rEr:�*1�D�"&r.r:���!(9# �K%"0�0(9�&(3#;"& ��!"&��� :�7�{#T(913���!���jDoD�;�� :(*�$'�"&� 13"0%���LDE�T?��r�@+��1�D:� "0���T� �{"�ED����!���"9�(S@{R(3#Ct`"&�!���kgu( �!�RDE(j��(S�0(9#T'�� *q� ¤v¶>£}«d±Hªv¨[¤#¦Rªv¤3���������0�������&�&U �jd��Ed���W�q

�R��WN� � B�;&@+�V(S��8 R��Bkq y!qL�\MN��%�(*@#LD:�.,zq �\f|;0(9# �\M�q ����(9#T#�(91*�6�\4`q ]�q ����1������*� �3q �!qL�|Hh����& :�wc{��B�q M�q Ä�¤@§T³ ¬ �.�NED� :"9%���a�+#�@A� :"9%�*ED��T�a(*�+�uDE;���T��13� ������19�u"�r`�����!���jDE�T(C(*��=�!� # �a1*"0%���LDE�T?���T�K�(3�T ��!���3D��T�m�A"�EDv�!���"&�(S@{R(3#\t`"&�!���kgADv;{���"&�!���{� |HV��(3#LDv;V����LD��T(8DE�w?��_ ���!"& �'�BjD�@�9'kg9(� E(S�0�$"&�!�T�3�3�`13"0�SDv :"&# # �*�5DE :�T(9#pq��d³R¯³A���������+��$������$W�&d��8�E�&WGq

�R��W�W � B�;&@+�V(S��8 R�>Bkq y!qL�`MN��%�(*@#LD:�K,zq ���5@#T# �� x�`M�q �`4.(S����>Bkq 4�q �zf|;0(9# �`M�q �`MN(S���6���!qwB�q Ä�¤@§�³ ¬ �!,."9� ��@%�(8D��*��� �9@A�w�{��6vDE :"&%+���$�(3�+�u�T��13� �$���019�!"&r\� �"3P+(*P# �>�����!���jD��T(!(*�+���!� # �u19"9%���LD:�w?�>�T�`�(3�T ��!���3D��T���{"�EDv�!���"9�(*@AR(3#�th"&�!���Ng��"&�!���{� |HV��(3#LDv;V����LD��T(8DE�w?��_ ���!"& �'�BjD�@�9'Gq��d³R¯³{���������+��$��/���0WX&Ul��Ed �0q

�R��W�� �`(3rEr:�*���!q*H`"j v�!"&��\D�;�� :(*�$'V(S��YDp;�.P �(3�w�kg9��� �R(5?&@!(3#T#+"&?�� N(*%�(3�w� 51�d³R¯�³{������������$��.�+�&Wl��8l$�EXAq�R��W�U � ��(j7R�8 �D�;�*�T#���B+�!"&# # �� x��BkqL�0Hh����& :�wc{��Bkq M�q ��MN�/�V(91*;�� x�$_-qL�9Hh�*� �7� � qL����"�"9�A�8 vP{�� E%�+,�qL��].(9�T :���$y!q Ä$¤@§+³ ¬ �+�NrEr��81�D|"�r

�6vDE :"&%+���!�#w@{Z� :"&%+�6ED��T��"&�eEDE �"&����T�>�"�EDv�!���"&�(S@{R(3#+t`"&�!���kg3Dv;�.��"&�!���{� IHK�8(9# Dv;!�E�+� D��T(8DE�w?��g$(h �(*����"&�!�T�9�3�DE :�T(9#pq��d³R¯³������������$�����&W�$l���� �3UAq

HA

L author manuscript inserm

-00243083, version 1

ÅdÃ

�R��Wd� � :"&��ED��*�T��+[bqL�A,.#T(* v�$�"3��+f5q ]�q �+_m(S�R"&����3q ��q��5������ xEDv(*����/�j%KD�;�`���w?�� :%+���SD\�&(8Dv(h"9�!�A"�EDv�!���"9�(*@{�(3#+;"& ��!"&��D�;�� :(S��'Gq��"i�¦X ¬ ����¤#²{�*��������� ������0U0d$�Ed��Aq

�R��W�� �h�� :�!�*�� x��Bkq ��q �&FA :�w���9<uq �!q �$�&���hHK�*� ���� x�$f�qL�9Hh"&rE�K(9�$�0y!qL� ��"9@��EDv(3(3# �$FNq �3q �&]. ��xD���# �8 R��_�q _)q&B�T# ���3D�P �(3�w�V�/�0rE(9 :1�D:(*���5D�;�� �� R�K"&rN�����!���jD��T(�(*���`1*"&%���LDE�T?+�Y�$�*1*# �T��&q�� i�¦X ¬ ����¤#²A�����������/ �������WN�8d���W$WGq

�R��Wl� Hh������� x7"&�� �!q � q ��F�(*%�(*���T�� �p;�T# # ��y!q ��_o� #T# �8 R��]�q M�q ���N#wPA# �*�G4`q �3qL�G4���'+�6���F\q [\qL��B�;�"9@��A�6� �!q Ä9¤@§s³ ¬ �k�\EDE :"9%���Cr:"& yh#T�*;�*�/�!�8 �� z��� ���(j7�K�T�Cth"&�!���kg� :(*�+�j"0�!� �3�*���|�j"9@�PA# �3�2P#2�T����O�+#�(91*��PA"��E19"3�3DE �"�# # �*�>DE :�T(3#Eq��Q¤v¶>£�« ¬ «@ÂvÁG���������+� %��WX�d��E�$���3q

�R��W � � _m@#w��(3 ����!4`q y}qL�>,."*D��K(3���,�q ��q � �Y(St�(j��>,5q � ��(*� �5'�1S�$��,zq H�q ��B+(*��"��>_-q � ��"&"��0'$�>4`q Ä]¤@§�³ ¬ �!�\ED� :"9%��� :�7�#T(319���!���jDNDv;�8 �(*��'ur�"j \DE :��(8Dv�!���3D�"&rI�!� # �!DE"^�!"����* :(�DE�`yh#T�*;+�*�T�!�* ���� ���(j7�jg�(! :(S���j"0�!� �3�*�u19"&�3DE :"&# #2�*�!DE :�T(9#pqyh#T�*;�*�/�!�8 �� ��� 7�8(&R�Y,I"�"9�{�� :(�DE�T?� BjD�@�9'Gq��d³R¯³{�����������$��/ $�N�8�&��l$���8dAq

�R��WX� ��(*�&%�AF\q <uq ��MN�T(3"���BGq �Kq �AMN�w@{�+4�qwBGqL�+MN�w@{�G,5q ��qL�A,\;�(3"��{Heq f�qL��MG@A��BGq 4�q Ä�¤@§;³ ¬ �G�|rErE�81�D:�"&r.�*EDE :"0%���u"&�e19"3%$��LD:� "9���!"�"����$(*���h19�8 R�7P :(9#�P+#�"$"��hr�# "&t��T�`y ��g9(�1*"3�3DE �"�#T# �*�KED�@A�&'Gq��Q¤v¶>£�« ¬ «)ÂvÁG���������0��%���&W�$���8�E�Aq

�R�8���� yhEDE;�(S�0(&�|BGq ��].(*��� x��M�q �KqL�G,\ E(9r D:��B�q ��B&D�(*��1*�*'����[bq ��qL� �h�*�LD�;��4hqL,zq �A4�(j����w�����_-q y!q ÄP¤@§'³ ¬ �GH`��%&;{�v�&"07�K�*EDE :(9�&� "�#�T�`� :"&?+�3\1*"&%���LDE� "0�Vr�"j �t�"0�!���!th�LD�;Ky���g3 ��6�@+# D�\"jr�(� :(���$"&�!�T�3�*�KED�@A�3'Gq�� ¤v¶>£}« ¬ «@ÂvÁG���������j�*%106�����$d�����WAq

�R�8��� � Hh"&%�� E?+"j RED:����qL� �`(3rErE�*���>q ��4���1S;�(3 :�����_�q ��H�@$����� �DE��[bq&H`"j ��!"&�+�h R�7�{#T(319���!���3DNDE;+�8 �(*��'!D�"��V(&�T�3DE(9�w�~13"&%$�0�LD��T?�r�@���1�D:�2"&�V�/�hth"0�!���!t��LDE;������!���jD���(`�E,."&1�;� :(*�+��45��?�� ��th��qd¾�«>ª ® £|³>¦R¤��#'�³R§1³R´d³>±#¤�� r Á;±�§ �)¡�¤#¥ � ������������, �h�����$lq

�R�8�&W � B1�;��+�*� ���� x�+M�q Bkq �$[G(* �#T"&th�+_-q 4�qL�&Hh���+���8 RR"&�� �!q ��qL�+FG"9%"��&(j���9q _-q&�|rErE�81�D:I"&rb�*EDE �"&%���! :�7�A#�(913���!���jD�D�;�� :(S��'!"&� :�*��"&�7�bDE"5DE(91* :�w��5�T�`�(8DE�T���3D:=t��LDE;Ky�# �S;�*�T�!�� x� \��� 7�8(&R�&q��Q¤v¶>£�« ¬ «)ÂvÁ � � ��+����j����d �j����UGq

�R�8���� B1�;��+�*� ���� x�CM�qwBkq �C[A(3 �#�"9th�C_-qu,I"&�KPA�T��*��DE(91* :�T�� (*��¬�3EDE :"9%���s R���#T(913���!���jDOD�;�� :(S��'��/���(�DE� ���3D: t�� Dv;yh#T�*;�*�/�!�8 �� \��� 7�8(&R�&q � ¦+¦ �,� � � � � ª#³+² � r ªv¨ � ��� � �!j����$��3�����8l$��W�WGq

�R�8�&U � 4��w%�(*@����y!q�B�qL��y5��& :�*� � qL� �h�*#T#T(j���]�q ��f\"9@1�;"&��1�3qL��F��8 E�*�1�3q �3q$<K"u(3�&���LDE�2"&��(3#�PA����*r:�LD�"�r.H`4�f�"9�~ :�*��A"&����D�" :�w?�(jEDv��%$�!�T��5�T�K�!���"9�(S@{R(3#$th"&�!���Kt`� Dv;`y �>q��Q¤v¶>£�« ¬ «)ÂHÁG���������0���.�&����U �j�EXAq

�R�8��d� [G(* �#�"0tz�$_-q 4`q �$MN(*;��T :� ���!q �!qL��F�"j�T ����� x���3qL����(*?��w%��"&����3qL�AB�1�;$��*� ���� x�$M�qL�&Hz@� �AB�q M�q*fN :��(8Dp�!���SD|"9@jDE13"0�!��"�rADE(31* ��w�{�D�;�� :(S��'����7�{���+�0«"&��(S�"&# �w�{"9� �"*D:�*�T� %���"*DE'&�A� (*�� %������� O"jrCD�;���@$P ���*1�D: th�LD�;¡yh#T�*;�*�T�!�� x� ��j� 7�8(&��&q� ¤v¶>£}« ¬ «@ÂvÁG� � � �����%/�&����&X��El$lAq

�R�8���� ]. :�w�3D:"0�$�$4hq �!q9�E�`�(91�D�"jr\�*EDE :"0%����Dv;�� :(S��'!"&�Kyh#T�*;+�*�T�!�8 �� \�$�/7��(j7�jg&(�r�"& E�!�T��DE;+�� :"&(&��5�¾1� r '�£�¶@Â;±6����������/�*��U��d���W$WGq

�R�8��l� �`(3rEr:�*���!qL�zH�(3(S�$�`_)q �`]\'�� x��zy!qL��f|(*�&%����K,�qL� �5@#T# �� x�`M�q��bED� :"9%����@A��*�zy�F �5�b�`(S����13"&%&��LD��T?�O���*13#2�T���g��?� ������19�Y"&r�%+����3�E����?+�� �"&���!���3DC�T�3D:�� :(91�DE�T"&�Gq��Q¤v¶>£�« ¬ «@ÂvÁG�#�������+��%�����X&UX��Ed&U�q

�R�8� � � � :�*���+�j(9# �*� � q y!qL�A4��7PA"3@A�R�T��A]�q y!qL�+Hh"0%0(S��AFbqL��].(* E��(*P�*� � �}q _�q ��B�;&@��K(*��� x��BkqL����"9;��7"&���Bkq Ä'¤@§u³ ¬ �NB$'&�h�jD�"&� :��# � �*r.(S��uR� ���K�*rEr��*1�D:5"�r\�"�EDv�!���"&�+(*@{R(9#�;"& E�!"&��*9g ��6x@{#LD:5rE �"&� DE;�`F�"�EDE�!���+"3�+(*@{R(9#��bEDE �"3%+����FG :"9%�*ED��T����3D:�� E?���3D�� "&�\f\ :�T(3#Eq y ´p±�§l¤@§ � (PÁ;¦R¤vªv« ¬ �T��� � �+����$��X �3W� ��q

�R�8��X� �b�*13�+4hq [bq ��fN ��w?�*�&�/�+_�q y}q&f|;�����rEr:�*1�D:I"jr\�*EDE :"0%���! :�7�{#T(91*���!���jDGD�;+�8 �(*��'!"&�>��7@ :"9�{�'�1*;"�#2"3%+� 1*(3#Ar�@��+1�DE� "&��w��%��T��"�EDv�!���"9�(*@{�(3#|th"&�!���mth�LDv;�(S��ut`� Dv;"9@jD5�����!���&D:�T(g�(u1* �� Dv��1*(9#b(S���D�;�*"& R�xDE�21*(3#\ :��?�� ��t!q��Q¤v¶>£�« ¹=±»Á$ª ® « ¬ ¡�¤#¥j��������+����$���$d����8��XAq

�R��U�� ��� ,I"&����*#T# �+_-q ]�q&FA;�(9 E�K(31*"&��w���Dv� 1�(*�+�`��;�(3 E�K(319"�# "9%� 1�?0(9 :�T(8Dv��"0�KP{�RDEt`�*���e���TrEr:�� R���3Db�*EDE �"&%���K� �"��9@1�D:*q ��¾ ¬ ¨l¦� ® ³R£�¯³;ªv« ¬ ��� � ���� �%��N� �&BA��W�UABGq

�R��UN� � 4��7P{"9@{7R�T���]�q y}qL� � :�*�����&(&# �*� � q y!qL���\���*#T(*����$_-q y!q3�|rEr:�*1�D�"�r�;+"j v�!"&��5 :�7�A#�(913���!���jDADp;�8 �(*��'!"0�}7�*#Tr:�� x�7�A"j �DE�*�1*"&%���LDE�/?���'��K�jDE"0�e*g! R�*�@#LD:�rE �"&� D�;��F�"�EDv�!���"9�(*@AR(3#C�bEDE �"9%�����FG �"3%+�6ED��w�����3D:�� �?���3DE� "&����FG�|FG�E�mDE :�T(9#pq¾ ¬ ¨µ¯³Rª@§l¤v£�¨µª3��� � ������&�N��l&W�EX�q

�R��U�W � ]. :"&tz�$�$f�q �3q �AB+1�;0�� :�3�$]�qL�&H`"j1S;&P{�� E%�$4hq ]�qL�&_a(91*M�@{��&'�3<�q �9q*4��7%&@{#T(8Dv� "&�K"�rN�*EDE :"9%���K R�819���jDE"& N19"&��13���3DE :(�DE�T"&�\�T�D�;�� :(8D�P� :(9���Gg&��rEr:�*1�D:\"&rN�@{vDE(3�w��*�`(*��& �"&%���K(*��K�*EDE �"3%+�*�!�7c��"��@ R�&q��Q¤v¶>£�«>¤#¦>²;«>ªv£�¨l¦R« ¬ «@ÂvÁA���# � ������. ��$d����E���Aq

�R��U�� B1*"*D D:�}4�q f5q � �x �qL�`4�"07��K]�q �`y5����� xR"0�$�>,�qL�zy� :1�;�� x� �!q [Nq�F�;0(* v�V(91*"&��T�+�xD��T13a"$ru�A�8 �1�@jDE(S�0�*"9@{ �6EDv :(3�&� "&#:gz(1* :"��R"0?�8 .ED�@+�&'K@{7�T��%!(z%�*#G(S��K(YDv :(*�R�$�8 ��K(3#G�'$vD:�����/�!13"&�K�(9 :� R"&�>th�LDE;�"& :(3#��!�T1* :"&��T�9�*�e�*EDE �(3�&� "&#Eq y ´d±�§t¤@§(�Á;¦R¤vªv« ¬ ��� � ��j��0�08�+l�d �j�E�0U{q

�R��U�U � ��(*��(�D:�@���� ��y!qL� ����(8DE(S���/� �eqL�����+���"9@{�*�A<uqL��[�@���(*'�(j��f�q ���TrEr:�� R���3D5�8r�r:��1�D:`"&rY"& �(3#N1*"&���:@$%0(�D:�*�C� �9@�T��>�3EDE �"3%+�*�(*��� DE :(S�R���� :�K(3#O�3EDv :"9%���� R���#T(913���!���jD)Dp;�8 �(*��'�"&��R�T�3�¡(*��s"9c{�2�j(�DE�T?�¡�@{R19���jDE�wP{�T# �LDv'�"jr�# "&th�E�$���$7�LD�'#T���A"9� :"*D��*�T�`�(3 �DE�T1*# �6\�/�h�"�EDv�!���"9�(S@{R(3#$th"&�!���Gqd¾�¨[£}ªv¶ ¬ ³^§l¨µ«d¦{�����������/�����j���8l�l��8�E��q

�R��Ud� ��%�� x�$��qL�&y`#T;����13� � �*#T(j��$_-q ��MN(91�@jD:���!q �$].# "9@1S;$�$_-q f5q �&4�"9@�&(*@jD:�9<uqL�����8 �#T(*�� �!q Ä$¤@§+³ ¬ � �`��rEr��8 R���3D���(9#�|r:r:��1�D:I"�r�5 :(9#h(S���-f\ E(*�R���� ��V(9#h�\EDE :"0%�����FG �"&%�*ED:�� :"0��a45��%�T�!���="&��BA���R�LD��T?�� Dv')D:"�y�1�D��T?�(8DE�*��FG �"6D����T� , y��!"&�+%FG"�EDv�!���"9�(*@AR(3#&��"&�!���GqSy�4�(*��&"&�!� �9�*�hf\ :�T(9#pq � £�§l¤v£�¨µ«@±#ª ¬ ¤v£�¢ ® £}«>¯�´��>³+±HªTU�¨[« ¬ �*������������0*���8lAq

�R��U�� B1*(* �(*P�w��\Fbq ��qL��y�#T;���+13� � �*#T(j7�\_-q �\F�#w@{��]\@ :��(*@A� � q �|fN(3� ��+�6�\F\q �|y5%�;+�8 R�\4hq �|y��T(31�;�\_�q��NrEr:��1�D:K"$r�"& :(3#.(S��DE E(*�R�$�8 ��K(3#��3EDE �"3%+���2� R"3%+�3ED:�� :"0��) R��%��T�!���{O"&��P{#2"�"���19"&(3%&@#T(�DE� "&��(*���rE�wP :�/�"�#T'R� O�T���{"�EDv�!���"9�(S@{R(3#th"&�!���Gq9y� :(*����"0�!���9�*�h19"&�3DE :"$# # �*�5DE :�T(3#Eq � £H§l¤v£}¨ «p±Hª ¬ ¤v£�¢ ® £B«>¯�´��+³>±#ª=U�¨[« ¬ ���# � /!&�/� 07�$����l��8� �+q

�R��Ul� �h��;���(9?�(3(* :(3��BGq ��B�T#w?�*�T :(&�&y!qL�0H�(S��(3#T(j�2yh#T(&��FG� �RDE� #T(j�$f�qL� ��� v�0(S�V(S�� �&y!qL�0Hh"&?�(8D Dv(j� �hqL�9H`(*�!EDE����$y!q Ä$¤@§+³ ¬ �+�NrErE�81�D�"&rN"& :(3#+(*�+�YDE �(*�R���� ��V(9#A�6vDE :"&%+���V R�7�#T(313���!���&DAD�;�� :(*�$'!"&�K�V(9 E��� x\"$rk19"&(*%&@{#T(�DE�T"&���r���P+ :�T��"�#T'7� ����/�0r�#T(3�K�K(8Dv� "&�(*���K��� E@+��# �w��2�0\(S��`#��w�A"9� :"*D��*�T�\�T�h�+"0vDE�!���"0�(*@{�(3#$t�"0�!����qd¢ ® £�«>¯�´� �³;¤v¯�«d±�§ �*�������3����%������8X���W+dAq

HA

L author manuscript inserm

-00243083, version 1

Å)Å

�R��U � � ���*13���7� �+y!qL� �5�!"&���*� � �KqL�+4�"9PA�8 �D:R"&��A,zq �+]."0�0(9����� �A]�qL� � @+�8 � :� �� :� � � "&���*(3%�(&�$y}qL�+4�(*�K(3�*�3"*D Dv"0�+[\q ÄJ¤@§;³ ¬ �A�|rEr:��1�D"&r�DE :(S�$����8 ��K(3#��*EDE �(3�&� "�#5(S��)"& :(9#Y1*"0� ��@%�(8Dv�*�)�6vDE :"&%+���-"&�-,��� ��8(91�DE�T?��� :"*D��*�T�-�w�) R�xDE�/�"�� ���2�A#�(913�7P{"mDE ��T(3#5�T�;��(3#LDE;$'hth"0�!���kqX¾�¨[£�ªv¶ ¬ ³^§l¨[«)¦{�����������/�����3�N�RW�W�U+� �q

�R��UX� B1*(* �(*P�w��KF\q ��qL� �Y%0�� x�}��qL�KF�#�@A��]\@ :��(*@{� � q��z��rEr��8 R���3DE� (9#!(&�R"&1*�T(8DE� "0� "&rm"& :(9#!(S��-DE �(*�R���� ��V(9#�"��3EDE �"3%+���{� :�7�#T(319���!���jDAD�;�� :(S��'ht`� Dv;`?���"9@{�D�;� :"0�KP{"����KPA"&# � R�� :� ���q�39³+¦Rªv¤@§ ����������� ��#$0�$U�W �j�E�&W�q

�R�8d��� _a�w'�(9%0(St�(j� �!qL��4�"�R1�;���9q �VBjD�(*��1*�*'$�$��[bqL��Hh�� E�!R�!��'+�8 �� �!qI_a���j �"9c'&� �"&%�*ED:�� :"0��a�T�3D��8 �r:�� R�6�th�LD�;�"&?�(3 ��T(*�EDE�� :"��2��� �"*DE�*1�DE� "&�K(*%�(9�T�ED�1*"& :"&��(3 v'h?�(&R"���(j��uq���³^§�� ¤#²{���# � �!��� ����0W�U�ElAq

�R�8d�� � �.D:�@$�0� �5_�qL�`B(9� Dv"0�YHeqL� ��@� �eq �`B�@��K�LDE(*�+�/�VBkqL� ��"9@�;�(3 �(j��H�q � ��� �;��T�!"9D:"��5f5q Ä ¤@§�³ ¬ �5F� :"9%�*ED:�� :"0��6�YP�@jD>��"*D�!�*�& x"9c+'&� :"&%+�6ED��� :"&��*�+�T��;+��PA�LD:\?�(&R1�@#T(3 \1*�*#T#A(3�&;�*7� "&�!�!"$# �*1�@{#2�6���5�7c�� R�67R� "&�!�T�>;&@�K(9�K?0(&R1�@#T(3 \�����"*D�;+�*# �T(3#13��# # *q � £H§l¤v£�¨µ«d±Hª ¬ ¤v£�¢ ® £}«>¯�´��>³+±HªTU�¨[« ¬ �*�������3��$/�&�&W�U��� �+q

�R�8d&W � Hh"&r:��RDv;$�+M�q �9q �$4�(*(9rE(�D:�$y!q _-q � �z�@1�;���3q 4�qL��F�(�D�;�(*�� �!q 4hq �AB+#�"0�eR��� �A,�q y!qL�$Hh(jR#T(S�}��B�q �5q9Hh"& E�!"&��5 R�7�#T(313���!���&DD�;�� :(S��'!th�LD�;u�*EDE �"&%���e"& .�*EDE �"&%���!�+#�@A��!�*�& x"9c+'&� :"&%+�6EDv�8 R"9���(913�RDE(8DE�`� .(&�R"&13�T(8Dv�*�!t��LDv;e�T�1* ��8(&��*�>���A�LDE;+�*#��T(&#� :"&# �Tr��8 �(8DE�T"&�K�T��D�;���"& ��V(9#��"�EDv�!���"9�(S@{R(3#$P ��8(&ED�q ��¾ ¬ ¨1¦�i�¦>²;«>ªv£�¨l¦R« ¬ ��¤@§ ³R´��� � � ������&U+d�d�X��E��d�q

�R�8d��� [G"&� �&(3 �D:���*q _)q �A,I"&#��/�$�A,zqL� �����+"�"�� �eqL� ���6� x�7@�c{���9q �+].��# �T(3 ����+y!qL�+[G"9@ E��� �� x��B�q ÄJ¤@§^³ ¬ �A�b�DE E(9�j�T"�#A(9���K�+ :"&%�*ED��8 �"&�� :��%&@#T(8D��bDp;�.� �"&# �Tr:�� :(8Dv� "&�K"jr�;j@+�K(*�`P :��(jED��7�A� Dp;�*# �T(3#+13�*# #�*q���¤v£H§t¨ ¬>r §l¤v£�¨ ¬ ��� � ������+��X������EX+q

�R�8d&U � ]��� :(9#/� �!q3]. ��8(&ED�1*(*��19�8 N(S��z;"& :�!"0��3�� :�7�{#T(913���!���3DADE;+�8 �(*��'K�T��DE;��_O��#2# � "&����"0�!���eB&D�@�&'Gq�39³>¦Rªv¤@§2����������� ��$��UN�8X���W+lAq

�R�8d�d� ����M\�w%��� �� R�67��]�qL�$�j� ��(8Dp;0(9�T x�*�$[bq �0[G"9@ E��� �� x��BGqL���5 EP�w��*#2# ���$4�q �jy�#2#�(9�8 �D:�$[Nq �0MN�6�$_-q � q ÄR¤@§+³ ¬ �,I"&�hPA�w��*�`;"& ��!"&�� :�7�#T(319���!���jDGD�;+�8 �(*��'!(S��K :� ��e"&r�P ��8(&EDN1*(S�019�8 \�T�!(`[G ����1�;!19"&;"& �D\ED�@�9'�"jr\���8l�d}th"&�!���Gq>¾ ¬ ¨[¯³Rª@§t¤v£�¨[ª3����������%�+���&W��U�+q

�R�8d��� 4���%� EDv�8 R�Af5q ,5qL�{y��&(9�!��A_�q 4`q � � "&# ������ �!q M�qL�G,.#T(* v�$�"&��Af5q ]�q+,."9� ��@%�(8D��*��� �9@{�T�+�K�6EDv :"&%����(3#2"&��*�+P�@jDZ�"*D.�T�1*"&�KPA����(�DE� "&�oth�LD�;a�!�*�& R"9c'&� �"&%�*ED:�� :"0��u(319�xDv(8DE�*�\�T�&;�wP{�LDz(3"& �DE�T1u19"&�&��*1�D���?+�!DE� ��@A�� :���!"����*#2�T��%a(3r D��� ��#T(&��V(#T���A� �`# "&th�� R�w��%!�w�Vr����!(3# ���!"&���+��'{*q � £H§l¤v£�¨µ«d±Hª ¬ ¤v£�¢ ® £B«>¯�´ �+³>±HªTU�¨µ« ¬ ��� � ����/�������$�8�&U�El��9q

�R�8d�l� � :"&��ED��*�T��.[\q �I_m(*�R"&�� �3q ��q ��,."&# �&�LDE�3� � q y}qL�|���T# # �RD D:�\��qL,�q �5B��+�8�T�3�� x�I[bq ��q �5BjD�(S�h�r��8 R�._�q �*q�y�� �"0x�{��1�D:�/?�6�"9P{��� E?�(�DE� "&��(3#GvD�@�&'!"�r��"�EDE�!���+"&�(*@AR(3#+;�"& ��!"&��.DE;+�8 �(*��'!(S��`� :�/�V(9 E'K� ���?���3DE� "&��"jr|1*(3 :�&� "0?0(&R1�@#T(3 \�&� ���(j7�jq� ¦>¦�½B¦^§t¤v£B¦���¤#²{�����������/�� � $��X�������U|�3q

�R�8d � � <K� # 7���$� �3qL�«]. :�w�3D:"&��«4hq �!qo�E�`�(31�D�"$r��+ :"&%�*ED��T� "&���3vDE :"9%���{�v�T���9@{19�*� ���@ :"9� �"*D:��1�D:�2"&�Gg)�'���� �%�' P+'� :"9%�*ED��8 �"&��o(*�����X����"& v� :"9%�*ED��8 R"&��m(S��)(9�3DE(*%�"&�+�/���P+'��!�*�j R"9c+'j�+ :"&%�*ED��8 �"&��m(913�RDE(8D��jqPi�¦>²R«>ªv£}¨l¦R« ¬ «)ÂvÁG��������+����/ ��0W��d�����W�q

�R�8d�X� <K� # 7���$���3qL�A]. ����3D�"9�$��4hq �!q����T?�� E%���3D.�/�K�(31�D."&r|� :"0%�6vD:�* �"3�+�h(S��>�!�*�j R"9c+'j�+ :"&%�*ED��8 �"&��`(319�xDE(�DE�K��FG :"9?�� :(9�."&��&@13# ��(3 \�!�LDE"0%���{��(31�Dv�T?�(8DE�*�}� :"*D��*�T�!��/�0(&R�hR�/%���(3# �T�$%�q���£H«>ª���³$§ ¬@� ª#³+² r ªv¨�� r�� ����������������j�I�8��d��$�������*q����&@�PW�����zy5@�%m� �q

�R�8���� 4��T13�*��_�q _�q � � E(*?�*��>y!q ]�qL��_a13,Z@ E E'�CB�q _)qL� � ��P$P"9�$7��M�q ��qL��]."9th����&�3q �!qL��_o13,."& E�!�T1*��K� q ,zq ÄS¤@§�³ ¬ �FG"�EDv�!���"9�(*@AR(3#.�*EDE �"&%���a(*�+�a�3EDE �"9%���{�2� �"&%�*ED:�/�m@{���(*���mW��'+�8(9 h �(8DE��"&rh19"9%���LD:�/?��1*;�(*��%+�u�T�a(C13"&;"& �D�"&r"�# ���� "��(S��(*���67��y��!�� x�T1*(9�`th"&�!���kg9fN;+� ��(9�!��F� :" ���*1�D�q � £�ª ® ½B¦^§l¤v£|¦���¤#²{�����������/�����j���8�&UN�8�EX�q

�R�8��� � _a�w����/�$�|_-q �3q�,."9�R� �$�8 �(8DE� "0�$`�/�~D�;��1*;"$��19�u"&r�"& :(9#\?$SqDE �(*�R���� ��V(9#\;"& ��!"3�+�VDv;�� :(S��'GgG(u R��?�� ��t!q���¡�¤»¹T£�«p²��¤#²{������������������������W�Aq

�R�8�&W � ]. E'�(*�3D:�{Heq �Kq � �h�� R�6�$��q HeqAB+�*# �*1�DE�T?+�K�6EDv :"&%���u ��819���jDE"& .�!"��9@A#T(8DE"& xSg�(9�e(9# D��� E��(8DE�/?�YD�">;"& ��!"&��� R�7�#T(313���!���&DD�;�� :(S��'Gq���£�«>ª�� r «>ª���i765¹ �)Uº¨µ« ¬ �H��¤#² ����� � ����$/� 07�$Ud��Ed0W{q

�R�8���� FA;�� # #T�w�{�� �!q y!qL�N]��8 ���;�(3 ����"�3q�y�� ��@?�(S�SD�P+ x��(jvD51*(*��13�� �DE ��8(�DE�!���3D5(9���m13"&%��+� Dv�T?��r�@��1�DE�2"&�kg�1�@ � :�7�SD����"&t`# �*�&%�(*���` :�*���(3 �1�;!�j�T R��1�D:� "0�$Sq�����³R§ ¬ ¾T³+¦Rªv¤v£�½B¦>±�§T�������������%��|��X����ElAq

�R�8�&U � FG(S%0(S���T�����2Hh� # # �0y!q �+,.#T(9 E���M�q �*q*F� :��#T�T�!�T��(3 v'V(&���*���!���3DN"�r�1*"&%��+� Dv�T?�5r�@��1�DE�2"&�!�T�`P :��(jED�1*(S��13�� ��(8Dv�����3D:CDE ��8(�DE�*�th�LD�;�DE(9�!"3c+��r����Gq�U�£}¤#³>±�§ �$¾T³>¦;ªv¤v£ �v¡�¤#± �;¢;£�¤#³^§ �T���������+������8��d$�El��Aq

�R�8��d� ��(*� ��(9�}��[\q�B�q ��B1�;�(*%����|Bkq ]�qL��_C@#T# �� x��_-q �*qL�G]."&"&%+�8 R���+��qL� ���K��(9# # �GM�q ��q � �� :"&"&%�# �*��?+�* �[G"& �D�@�'����_-q ��q ÄP¤@§³ ¬ �N���`�(9�� ��!���3D�"�r�19"&%����LD:�T?+�Kr�@��1�D�� "9���T�Cth"&�!���C x��13�*�/?�T��%~(9� �:@+?�(*�3D\DE :��(8Dv�!���3D�r�"j ;0�/%�;{�� :� ���P R�8(&ED�1*(S��13�� 8g;�T%&;{�v��"���I?�8 R�@{.EDv(*���&(3 :������"�7��1S;���!"3D�;�� :(S��'Gq�� �#��³$§ ¬ �p¾º³>¦Rªv¤v£ �)½B¦>±�§ �T��� � ������/���&W|�8��� �q

�R�8���� <K�T1*��*# 7����\fYqL�\M�@r����T��\��q � qL�\4���%$%$7�\]�q M�q �.,I"9c{� �!q y!q �.,I :"&"&��\f5q H�q�4.(3#T"9c� r:���+��;�'�& :"$1*;�# "& :� �$�6�\(m��*#2�*1�DE�T?��6vDE :"&%+���� :�*13�7�jDE"& �!"��9@{#T(�DE"& 8g)R(9rE�xDv' (j�R�*���!���3D�"&r¡�8rEr��*1�D: "0��1*"&%���LD���?+��r�@+�1�DE�2"&� (S����!"$"����T��"�EDv�!���"9�(*@{�(3#Kt�"&�!����q��T±»Ásª ® «d¦R¤v¶>£}«>¤#¦>²R«>ªv£}¨l¦R« ¬ «)ÂvÁG��� � � ��$������8d���W �+q

�R�8��l� �`(3rEr:�*� �!qL� �z E@�7%�� x� �!qL�\B�(* v��(3 :�\BGqL� � E(3�9'� �!qL��].(9 E :�RD D:��1*"&�$�"& x����qL��,."9c{� �!q y}q Ä=¤@§P³ ¬ �b,I"3%&��LDE�/?�!r�@+��1�D:�T"&�m�T��"�EDv�!���"9�(*@{�(3#$th"&�!����DE :��(8D��*��t`� Dv;K :(3#T"9c�Tr:���+�jq�� �)i�¦X ¬ �#� �#��¤#² �K���.�����j�� ��0�|��W�&l������Aq

�R�8� � � MN�LD DE# �RD�"&����h��(3 v���'�K_-q f5q � ��ED� :"9thR�+�/�z<uq M�qL�!,I"3cA� �!q y}qL�}4�"���PA�8 v%�K_-q ��qL�`Hz@0 v��KFbq �!q`B+�8#2�*1�DE�T?���*EDE �"&%��� :��13�7�jD�"j ��!"��9@{#T(8Dv"j R*g�DE� ��@��(31�DE� "0�$\(S�����"*D����3D:�T(3#+r:"& b,�<^BK�� :"*DE�*1�DE� "0��qd¾1� r '�£�¶@Â�¡�¤#¥j�����������������$��X��E���Aq

�R�8��X� B�;�� Et`�T��N]�q ]�qL�Nf|@#T(*����� �|fYq �Ey�����2P+(31����`�6EDv :"&%���m R��?�* x��6`19"&%����LD:�T?+�e�$�*rE� 1*�LD:K�T�+�3@+13�*��P'm(�%"0�0(9��"*DE :"9��/�{� :��# ��(j7���$%e;+"j v�!"&���(S%"&�� ED|�T��th"&�!����th�LD�;�# �*� "&�K'"$�K(8D�(�@jDv�8 �� � 7�*��13"0�K�!���jD:*q � �J¾ ¬ ¨l¦ �di�¦+²R«>ªv£�¨l¦;« ¬ �v��¤@§1³R´ �T�� � ��+���/���&W+d&Ud��EXAq

�R�8l��� B�T�`�{7"9�$�$��qL�$4.@�P�w�� � qL�,I#�'$��6�+,�qL�$4�"9PA�8 �D:R"9�� �!qL� ��� ��"&����*#2#/�$M�qL����"9��67��_�q Ä$¤@§+³ ¬ �$fN;�� :"�#2�Y"$rN#T"�1*(3#A�*EDE �"&%���P� "��'��3Dv;�*�� \�T�K�K(3# �*\(*�+�hr����V(9# �3*qd¢$£�¤#¦>²+± �)i�¦>²>«>ªv£}¨l¦R« ¬ ����¤@§ ³R´ �����������0��������� �9U� �q

HA

L author manuscript inserm

-00243083, version 1

Å �

�R�8l�� � ��(*��FG"*D D��*#wP{�� E%�;�o��qL� � "����K(j�� R�6�«B�q � �5(*@r��K(*�� �3q _)qC].��"&(9?�(3�T#T(*P#2� �3EDE :(9�&��"$# (S��s(*��(3 �"&�K(8DE(&R��%+���{��"�#w'��!"& E�+;� �� (9 :�m���RD:�� ��!�T��(*�3D:�"$r`P"&��=�!�T��� :(3#5�����GR�LD�')1*;�(9�&%�3��T�«�!����"&?+�8 �l��o'��(3 R�"&rK(*%�&q�� ¾ ¬ ¨l¦i�¦>²R«+ªv£�¨l¦R« ¬ � ¤@§1³R´�����������������+����l�d�� ���6q

�R�8l&W � Hh"&%�� E?+"j RED:�5��q � ��� �7(*%�� x��,zq �5]\@+�3%+�6�5_�qL�`B��!�LD�;��y}q �!q�B�� E@�� # ��?�*# C"&re�*EDE �(3�&� "�#z(*��aD��*EDE"�ED��8 �"&��a(S����� :r:"& ��K(*��13� �T� �$��r�r:�� :���3D 13"&%$��LDE�T?� ��"&�K(3�T� �w� ;��(3#LDv;�' �8# �$�8 R#T' �!��� (S�� t�"&�!���kq�T±»ÁJª ® «p¦R¤v¶>£�«>¤#¦+²R«>ªv£�¨l¦;« ¬ «@ÂvÁG���������0�*$���&U�$d���WN�*q

�R�8l��� B����(*��(9 :"9��%� �!qL� ��(S����(jR(9����%�\BkqL��F�"9@��&%�?�(3 :�w��A<uqL��F�# "&'&P�@jDv x�\B�q ���5��"&�K�$@�3D�;&@ �(*��\BkqL�1�7(*���:@+�K :(j7��Fbq Ä=¤@§�³ ¬ ������"0%���"9@{.�*EDE �(3�&� "�#A�/�!�*# ���� x#/'!�T��&�T?� �9@(9# *g&13"&%$��LDE�T?��(S���K��"&�19"&%&��LD:�T?+�-(&�R"&13�T(8Dv� "9�$Sq � £}ª ® ��Q¤v¶>£�« ¬ �/����������%���+� �3d��EXAq

�R�8l&U � _a(S�0#/'$� �3q �3q �N_o�8 �1�;0(9�3D:�\,�q y!qL�"�R(31*"9P{7� �!q _�q �IB��K(3# # �IBkq y!qL�|]��*# # � �!qL�N[��8 �����|_-q Ä�¤@§.³ ¬ �\������"&%���"9@{}�3EDE �"3%+�*�# ��?�*# \(*�+��yh#T�S;�*�T�!�� �� \��� ���(jR��(9�!"&�&%h�A"�EDE�!���+"3�+(*@{R(9#Kt�"&�!���kq�� ¤v¶+£�« ¬ «@Â�ÁG���������+��%��� �&�����El+q

�R�8l�d� fN;�(9#/�\M�q �*qL�|fN;�"&�K(j��\4`q � qL�\_m@#w��(3 ��0�\4�qL��B�(S�0"��\_�q � � �@���&�K(9�$�\_�qL��B1�;&��*� ���� x�\M�q��bEDE �"3%+��� # ��?�*# >��"=�"*D1*"& : :�*#T(�DE��th�LD�;V�/�K� :"&?+���!���jD��T�K13"&%����LD�� "&�Gq � £�ª ® � ¤v¶>£}« ¬ ���������������&W��X$����WGq

�R�8l��� � �*�� x#T�T�$%$7��_-q ��qL��M�(*@����� x��M�q �9q ���&� ��"&��%��[bq Heq ��4.@+� Dv���&PA�8 v%$�^y!qL�CBjDE� ��������f5qL�>?�(*��B$t��2�xD�����&�3qL,�q Ä]¤@§�³ ¬ ������"0%���"9@{`�*EDE :(9�&� "&#N(*��� :� R�m"&r5�����!���jD���(��T�Ct�"&�!���a(*�����!���kg+D�;�!4�"*D D:�� :�&(9��BjDp@�&'Gq � ¦>¦&� ¤v¶+£�« ¬ �1��������%/ ��+���&l����8dAq

�R�8l�l� 4�(&��h@AR"&��KB�qL��<`(jx�V(S�$�z]�qL�h,I(* :# EDE �"&�!���!qL���5# �R"&��zf�q����01* R��(jR�*��#2��?�*# m"&r�(j�& ����"&13"& �DE�T1*(9#K(*���%"0�0(9�&(3#;"& ��!"&��*\�T�K�!�T# �YDv"`�!"����� :(8Dv��y`#��S;�*�T�!�� x� I�&�/7��(j7�jq�'�¤v¯�¤#¦^§�(�¤v£�¨l³^§l£�¾�«)Â;¦ '�¨l±H«>£B²������������� j�+l&U�EX+q

�R�8l � � Hh"&%�� E?+"j RED:����qL�!� ��#T# �T(9�!��2�9q ��]\@�9%�*�u_�qL�u].(9 E���xD��"&���M�qL�~,I"&�`P :�w�1S�$��_-qL�CB$�!�LD�;��y}q �!q�B�� E@+� Dv"6Dv(3#DE�*ED:"�EDv�8 R"&���� \# "&th�� N�T�K�!���Kt��LDE;Ky�# �S;�*�T�!�� x� \�$�/7��(j7�jq�� ¤v¶>£}«>¤#¦>²R«>ªv£}¨l¦R« ¬ � 3=¤@§l§ �����������j�*$�$���8�$��� ��q

�R�8l�X� Hh"&%�� E?+"j RED:�+��qL�&���T# #2��(9�!����3qL�A,."9�`P :�/�1*��+_-qL� ��(S?�����B��!�LDv;$�{y!q&_ ��(jx@ :�w��%e7�8 v@� "��*EDE �(3�&� "&#G�T��th"0�!���et`� Dv;yh#T�*;�*�/�!�8 �� z��� ���(j���g�D�;�>�T�K�{"& �DE(*��13�K"&r\DE;�!7���R�LD:�/?0�LDv'�"&r\D�;�K(j7R(*'C�!�xDv;"��Aqdi�¶>£���i�¦>²R«+ªv£�¨l¦R« ¬ ����������1��������l��El&W�q

�R� �j�� ]."&th����+4hq M�qL�$�:R#T��'���3q F\q �0y�D���T�7"9�$�$4hq M�qSy��!(&�R"&13�T(8Dv� "9�!"�rN�*# ��?�(8D��*�K��� E@+��%"&��(9��"*DE :"9��T�!19"&��13���3DE �(8DE�T"&�\(9��yh#T�*;�*�/�!�8 \�&�/7��(j7��5 ���Q¤v¶>£�«>¤#¦>²;«>ªv£�¨l¦R« ¬ �������������$����d��8� U�q

�R� �G� � ]."&th�����4`q M�q �^B��!�LD�;�>_-q y!qL�KH`(3 : �� ��KF\q M.qL� �5@�P�(8D�� ��q �!_o(* �DE�w���>4hq <uq ��,\(jEDE��# #T(*�+�/�>4`q �9q Ä]¤@§�³ ¬ ���N#T��?�(8D��*�#w@jD:���T��T�9�T��%a;+"j v�!"&��u��c$� :�*�7��"0�a13"�# "&1*(9# �T�3�3`t`� Dv;m���@ �"&�`?&@A#T��� :(*P+# �KDE"myh#T�S;�*�T�!�� �� K��� 7�8(&R�>�(8D�;+"�# "&%&'Gq��� ¤v¶>£}«d±Hªv¨d¡�¤#±6�*����������0 �$��d���U� �+q

�R� �3W � ].(3 E ��xD D��E,."&���+"j R�A��q �A_=@�8#2# �8 R���3q ��q � �h"0�e_m@$;# ���� �!q � qL��MN(*@�%&;#2���� � q y!qL��B1�;&��*�2���8 R� �!q M�qL��B�(* �DE"& :� �� �!q �*q�MN"9t# ��?�*# C"�r��*EDE :(9�&� "�#�(9 :�a(&�R"&13�T(�DE�*�)t`� Dv;�?�8 �D:�7P �(3#�rE �(31�D�@ ��6��T��"&# ���� ��!����5P$@jDK�+"6D^th"&�!���kg\D�;�o4�(S�01S;"]��� E��(3 ���">BjD�@�9'Gq�� �^¾ ¬ ¨t¦ �)i�¦>²;«>ªv£�¨1¦R« ¬ �}��¤@§1³R´ �T�������������%��&WN��X���W�Aq

�R� �j�� ����'��f5q �*q � ���� ���(jR(9#�"��$Fbq �KqL�&].(*�&���$��q*����T�����!�2"�# "&%�'K"�r�P ��8(&ED�1*(*��1*�� 8q�39³>¦Rªv¤@§ y ¦Rªv« ¬ ���������j��$��N��������U�+q�R� �3U � �5@1�;�*# � � q y!qL�Gf|(*�&����&P(*@+�!�k,zq � � :�*�����(S��NB�q MZqL��4��*���T1*��+<uq _-q+,\(*��?�(3 :�T(SP�T# �LD�'u�T�!DE;�z;"& ��!"&��(3#NEDE(�D�@{5"&r

�*# ���� :#T'Oth"0�!��� (j7R� ED��T�~Dv;� ����13� 7� "&�~D�"m(3�&�!�T�+�/vD:�� K�3EDE �"3%+���$ 5 � �Q¼�«>¯�¤#¦>± �J �¤#³ ¬ § ® ��(¤#¦>² ��U�³+±H¤#² �$��¤#² � ��������&������������X����8�Aq

�R� �jd� ]��� :# �/�j%+�8 R�A��q � qL��FG"*D DE�� x�1�9q [bq�MN"9t�]�"��0'~_a(&����������cm�T�m�����!���jD��*�~"9@jDp�(8DE�T���3D:*q*� � � ¯ �7(�¤v£�¨l³^§l£ � r «>ª � � �# . ��j� ���+X�l&��� �q

�R� �j�� ��(3 ��&#�(Sth� � q _-q9FA@jD Dv���&%KPA"��&'>th�*�T%�;3DN(S���!"�ED��*"3�A"& :"�R� ��T�3D:"`�A�� x����1�D��T?�&q � ¯ ��� �J¾ ¬ ¨l¦ ��Q¶R§l£ � ��� � �����. ��$U���+BA��+Bkq

�R� �jl� H�@(S�j%� �YqL��H�(*�&��T�R"&��|Bkq ��q ��,."&#T���LDE�3� � q y}qL�|B3DE(S�h�r��8 R�A_�q �*qL��H�@��3DE�� x� �Kq �3q ��_m(*�R"0�$���3q �.q Ä'¤@§s³ ¬ � �5@�(9#k��rEr:�*1�D�"&r�th�*�T%�;3D�(S�0�`t`�*�T%&;SD�%�(3�T�K"&�`P :��(jED�1*(S��1*�8 N �� ��Gq��d³R¯�³{��� � �!���$10 �+����U��l$�����*q

�R� � � � ]. :�RD D:��_�qL��].(*c�7��&(3#2�6�\B�qA_a"*D�;+�8 �;"�"&�u(9����!���!"� v'kgA(u ���?0�2��t}q+�T±»ÁJª ® «d¦R¤v¶>£�«+¤#¦>²R«>ªv£�¨t¦R« ¬ «@Â�ÁG�1�������&�1$��3�N����X$��&WGq

�R� �jX� �b�`@�&(j���9q _)qL�+,\(*@#T��'���3q y!qL�+M ��@���%�+]�q _-qL��].(S@�� x� �!q ,�q �+,\@$�K�!�T��%���Bkq 4�qL���5@#T# �� x�+M�q Heq9]."&��5�K(j7.(*���`P ��8(&ED1*(*��13�� N ��/x�V�T�K"�# �$�8 �t`"&�!���kg&���TrEr:�� R����13�3|P�'!EDE(S%0��(8D��&�T(*%��+"0��/Sq�����³$§ ¬ ¾º³>¦Rªv¤v£�½B¦>±H§ �*�������3���/ &��X������E��q

�R�8X��� ]\@� ED:� �!qwBGqL�AMN(3,I :"&�wc{��y!q �5q ��].(3 �#�"9th�+��q ��qL�+��;�� D��*�G��q �&�����/7��+<uqwBkq�]."0��`�!�T��� :(9#k�$���$7�LDE'u(S�0�>P R��(jEDI1*(*��1*�8 :� ��K�T�`�"�EDE�!���+"3�+(*@{R(9#�t`"&�!���Gq���¾ ¬ ¨l¦�i^¹T¨l²;¤v¯�¨[« ¬ ���������3��%���$U��8l���W�WGq

�R�8X�� � ,.(S@#T��'$���3q y!qL��M�@+1*(j��$[bq M.qL� �5@+#�#2�8 R��M�q HeqL� ��"&%3D:��_�q f�qL��]. E"&tz��8 R�3� q�B�qL�,Z@��K�!�w��%��AB�q 4hq9]."&��5�!�T�+�8 �(3#A�����7� Dv'(*���� :� ���"&r>P :��(jED�1*(S��13�� u�w��"j#2���8 �th"&�!����gbD�;+� ED�@A�&'�"�r�"�ED:�*"9�A"& :"*DE� 1OrE :(91�D�@� :�**qzBjD�@�9'�"&r �zED:�*"9�"& R"*DE�T1[G E(91�D�@� :�*\4��*���(3 �1�; � �"9@��kq��d³R¯³{���# � ����$ 0�3�N��U��&U+� �q

�R�8X&W � ?�(*�!���� �z# �Tr D:��_�qL��MN(9�xD��,zq ��q �+,."&��PA�� :%$;$���3q ��qL�0Hh"&rE�K(3��$y!qL��F�"&#/7�&Heq y!q&]�"0����!�T��� :(3#������R�LDE'K(9��5DE;�� :� ��e"&rP :��(jvD�1*(*��1*�8 �g8Dp;��45"*D DE�� :�&(9��B&D�@�&'Gq}U�«d¦R¤3������������ *$�&WN�&�8�E�Aq

�R�8X��� �N;�(*��%� �eqL�+[��*#/7"&�� �!q f5q �+�N#T# � R"&��+4`q ,zqL� �Y ���%�� x�+]�q ��qL��B�1�;�(8DE�S�0�/�$�{y!q � �`"& E%�(*����3q [\q ÄJ¤@§^³ ¬ �A]."9��z�V(&�.(9���hDv;� :� ���"jr|13"�# "9��1*(*��13�� b(9�!"&�&%K�A"�EDE�!���+"3�+(*@{R(9#At�"&�!���kg9DE;+�Y[� :(S�!�T��%&;�(3��EDp@{�&'Gq � ¯ ��� �di^¹T¨l²R¤v¯�¨[« ¬ �����������3����%/ &����8�ElAq

�R�8X&U � �`(3rEr:�*� �!qL��]. :"&t��+�8 R�� q ��,I(*@#T��'���3qL�GM|(*@����� x��M�qL��Hh(* E :� ���f�q$yh�R"�1*�T(�DE� "&��PA�xDvth�*���uPA"&��}�!�T��� :(3#|�������LD�'~(S��1*"&%���LDE�/?�5���*1*# �T����T�!"&# ���� Cth"&�!���Gq�� � � ¯ � (¤v£}¨l³^§1£ � r «+ª������ � � ���10*�����8l��$� �3WAq

HA

L author manuscript inserm

-00243083, version 1

Å �

�R�8X�d� �N;�(*��%� ��qL�NB+�6�;�(3�& :� �|BkqL���N#T# � R"&���4hqL,�q �AH`�*�8 ����$��f5q ��[G��#�R"0�$� �!q fYq+]."9��`�!�T�+�8 �(3#N�����7�LD�'u(*���?+�8 vP(3#��!���!"& �'�T�`�(3�T ��!���3D8g$fN;��T :�`<K(8DE�2"&��(3#AHK��(3#LDE;�(*��`<`@jDE ��LDE�T"&�e��c+(*�!�T��(8Dv� "&�~B$@ E?���'Gq � ¯ ��� �+i^¹T¨l²R¤v¯�¨[« ¬ �����������3� �*%���Gl�X�d$��j�&WGq

�R�8X��� M�@� �+M�q ��qL��BjDE"9��*� �!qL�A,.(S@#T��'$���9q y!qL�$Hh�T# # �2�8 R�+f�qL� �h(9rErE�6� ��q&]."&��z# "��\� ��*���T1�D:�x@�P{7� �3@A���3DN19"&%����LD:�T?+�����*13#T�T�+���T�"�# ���� �th"0�!���kg8Dp;�YEDp@{�9'!"&r�"0vD:�*"9�A"j �"*D:�T15rE :(91�D�@ :�**q�� � ¯ (¤v£�¨t³^§l£ r «>ª3�*����������%/�$��� �j��U��q

�R�8X�l� ��"&;��EDv"&��,zq ,�q �*qL�+B#T���!����&(&�,zq ��q*F�(�D�;�"&%����3��/I"&rk"�ED��*"9�{"& �"0��/Sq�U�«p¦R¤3���# � ����/� 07�|��X+B{��W$WB�q�R�8X � � ��(3#T�T�$%$���3q 4�q ��]. ��w�SDv"&���M�q y!qL� ��"��T%3D:��M�q [\q �\����� ���\<uqwBGqL��,."&(�DE�67��4�q �3q �._o(3#T"9��6� �!q ��q Ĥ@§�³ ¬ ��4��/x� "&r`P ��8(&ED

1*(*��13�� N(S�!"&��%`t�;�LD:��t�"&�!���!r�"�#T# "&th�T�$%V�T�+�3@+13�*�`(*P"& �Dv� "&�Gq � ¯ �� ��i^¹T¨l²R¤v¯�¨[« ¬ ����� � �����*�����l$��� �j�+q�R�8X�X� FG�RDE :(S���/7�5<uq M�qL�5�� :�7�R1*;�`_-q 4`q �`�N v�$vDE�8 R���!q M�q �`_o�T�T��3�`4hq �`_m@� :(9� ���3q �>B+���`PA�8 �%�5<uq Ä�¤@§Q³ ¬ �K���0r�#w@{����13��"&r

� :�7%���(9��1*'!(9���e#T(91�DE(8DE�T"&��"&�e7�8 v@��(S��`P R��(jED|rE#�@A� �>�6EDv :"&%����#2��?�*# 3g$�T�h�A# �T1*(8Dv� "&�.r�"j |P ��8(&EDN1*(S�13�� b �� ��Gqv½B¦^§ �� �^¾º³>¦Rªv¤v£ �T��� ���!���/�&�+d �jl��EX��*q

�TW���� fb�LD�@A����N E�EDv"jrEr:�\M�q �\F��8 ��8�3� �>q �.,I E(*�!�� x� �!q ��qL�|H�(3 �#T"3th�I]�q M�q �\].(* �"9�$� �9q y!qL� � ��*���jPA�� :%�\��q 4`q�_a�7�$vDE E@(9#.(*��� :�7� :"$�3@+1�DE�T?��rE(31�D�"j R\�w�V ��*#�(�DE�T"&��DE"K"&?�(3 ���(S�V1*(S��13�� N :� ��GqBU�£1��¾º³X¦;ªv¤v£8���������3�����$l���U��WN�*q

�TW��� � ,."&# ���LDE�3� � q y!qL��[A E(9�*� �8 R�&y!q M�q*_o"&���*# ."&r�P :��(jED�1*(S��13�� b�;"&t)D�;�(8D� �� ��V� .7�xD�P$'!��?���3D:\"&rN�8(9 :#T'K# �Tr:��g�� :��?+���SD��T"&��*rEr:"& �D�|�h@{vDN�;���r D�r�"&1�@{*qd¾T³>¦Rªv¤v£ �@iR¹T¨l²;¤v¯�¨[« ¬ �)U�¨l«>¯³R£ +@¤v£|± �@��£�¤#¥ � ���, � ����+��d���l��El��6q

�TW�&W � FG�w��*�N_�qL,�q � �5 :(9��#T"��|_-q �!qL��Hh����$�8 RR"&��N]�q ��qL�N,I(j�(*%� E(S�0�$�6� �3q f�qL��Hh"���# � �>q � qk� H`"j ��!"&��(9#/�+ �� ���rE(91�D:"& R��b� P0 ��8(&EDDE� ��@��(*%�3��(S���YD�;+��(*%+�3�E�T��13�2������13�5"&ruP ��8(&ED�1*(*��1*�� 8q���³^§1¶>£}¤3��� ������ ��� ��$l���l��El��+q

�TW���� FG(�D�;�(*�� �!q 4`q � ���@1�;���*q 4hq ��Hh�*���3q+]b ��8(&ED.1*(* �1*���+"&�V(��RD:�2"�# "9%�'kg+1�@ � :���3D\���"0th# �*�&%�`(9��>���t��T�7�T%�;3D:5�/�SDv"VDv;��*rEr:�*1�D:I"&rN R��� �"��9@1�DE�T?+��(*��};"& ��V"&��(9#A :� R�!rE(91�D:"& R.�w�KP{#T(91��!(*��}t�;�LD:���A"9��@#T(8Dv� "&�*q>¾T³+¦Rªv¤v£8���������������\��W�&����q

�TW�&U � 4�(S@jD�(3#T(*;3DE� ��_-q �.y�#wP(S��67� �>q � ���T �DE(S�!"����9q �IFG(9#��K%� R������3qL�.H�(S@��&�0(&���3q �IHh���T�"&�+���$� �Kq F\qbM|��rE�RD��T�!�C�!���{EDE v@(3#(31�DE�w?�LD�'A�E�E�T��&� 1*(�DE"& N"&r�P :��(jED�1�(*��19�8 N �� ��Gq�i�¶+£ �,� �vi^¹º¨l²R¤v¯�¨l« ¬ � ���# � ����������l���WdAq

�TW��d� <`%&@'+���$�zf5q �!qL� ��"9��67� � qL�}B(S�hP �"�"&��zFbq <uq ����;��LD:�*�K,�q FNq �����*#2#�'�zFbq �3qL�z�N� ��V(9�� �3q y}q��NrEr��81�D:="&r~�*EDE �"&%�����c$�{"��@ ��5(*��K ���� R"&�9@{1�Dv�T?�5rE(31�D�"& x."9�KPA"9��5�!�T��� :(9#~�$���$�� Dv'!(*�+�K"0vD:�*"9�A"j �"*D:�T1�rE �(31�D�@ ��6Sq � �^¾ ¬ ¨t¦ �@i�¦>²R«>ªv£�¨t¦R« ¬ ���¤@§1³R´ �/� � � ���*�/�&��Wl&��X$����UGq

�TW���� [G"9c{���!q _-q ��_o(*%�(3�*�w��� x���3qL�AB$;��8 vth�T���4`qL�AB+1*"6D2D:���9q ,�q ��F�#T(8D�"��,zq ,zq �9<K��?�LD D:�$_-q Ä^¤@§+³ ¬ �4����+ :"&�9@{1�DE�/?�513"& : ��8#T(8D��*."&rP"&����K(j�\�w�!�*# �$�8 �#T'Kth"&�!���Gq$BjD�@�9'!"&r ��EDE�*"9�A"j �"*D:�T15[G E(91�D�@ :�*\4��*R��(3 �1�; � �"9@��kq�� �@U�«p¦R¤�����¨l¦;¤v£ �v¡�¤#± �T���# . �����+X����8� ��q

�TW��l� _a�T1*;�(9�*#/7�"&�� �>q ��]b(9 :"9��1�3q y!q � ��"9;j�+�*# # � �KqL��FG�� x7R"9�$����q ��M ��@��$%�;�(3# # �\B�q ��(3 :�T(�DE�T"&�C�T�eDv;�!��r:rE� 1*(91�'�"&r�;"& ��!"9�{� :�7�#T(319���!���jD.DE;+�8 �(*��'a�w�~D�;�>� ���?���3D:�2"&� "�r5;��w� rE :(91�D�@ E�&qNB+th�*�$�/x;mHh�w� [G �(31�D�@� ��uBjDp@�9' � :"9@��kq y ±�§t¤v« ¹T«>£�«p± �½B¦^§ � ��� � ��������+d3U+���E�Aq

�TW� � � _a�T1*;�(9�*#/7�"&�� �!qL��].(* :"9����3q y}qL��[A(3 E(S;��K(*�����]�q �eqL��FG�� x7R"&�����q ��M ��@��$%�;�(3# # �|Bkq �� E(3# ��13"0�SDv :(31*�7�jDE�/?��@A��`(*��� ��/��"&r�;����!rE �(31�D�@+ :�&g3(�1*(&R�*��1*"&�3DE :"�#AED�@+�&' 3.³>¦Rªv¤@§ ��� � � 0�� �%/ �����U ���8��UGq

�TW��X� B��!�LDv;$�>,�q y!qL�K_a1*1*#2�8(9 E'�!,zq y!qL�K_=@� :�&"&1*�� � q y!qL�����2#/�;�T :�*�Kf5q ��q �}]\@1���t�(3#LD��8 R� �!q �!qL�}]. :�RD:���'�KF\q ÄM¤@§�³ ¬ �MN�Tr:�*# "0��%!�6vDE :"9%���!�7c��A"0x@ :��(*��`13"&%$�0�LD��T?�I�{�� :rE"& ��V(S�13���T�K�*# ���� :#T'Kth"0�!����q}U�£B³;¨l¦ �R¾�«@Â;¦ �T��� � � +�� �����W+������� ��q

�TWN�8�� _a1*MN(S'�N4�q <uq �N_m(S�0� �|Fbq _)q �|M�'&��RD:7"07�b,zq � q+<`@#T#T�w�(3 �� Dp'a(*���~#T(�D:�>�!���"9�(S@{R�!(9 :�>(j�R"&1*�T(8D��*��th�LDE;m���*1* R�8(&R�*�1*"&%���LDE�/?�5���*1*# �T��&q�� �Q¤v¶>£�« ¹=±»Á$ª ® ¨l³^§t£[ÁM¾ ¬ ¨l¦�� ¤v¶>£�«p±Hªv¨ ���������+�/��%��������8�ElAq

�TWN��� � 4��T1*;�(9 :����|_)q � �5@�;� �>q ��H�(* ��9'$�|4hqL�A� (3���th"& �Dp;$�|_-q�MN�wr:�RDE�T�!��13"&%$�0�LD��T?�>r�@��1�D�� "9��(S��eDv�T�!�T��%a"&r.DE;+�K��(8D�@+ :(3#�!���"&�(S@{R�&q��Q¤v¶>£�« ¬ «@ÂvÁG��� � � ��%/ &�+��� �j����UGq

�TWN��W � FDE"9�� �KqL�+].(3 E��"&th� �!qL�$Hh�7@+�$�+4`q3[��8 �DE�T# �LD�'!(*�+�K�&@�KPA�� b"�r|1�;� # �& :�����T�K�(�DE� �7�SD�.t`� Dp;!yh#T�*;+�*�T�!�* x� I��� ���(j7�&q � £�ª ®¼�«+¯�¤#¦���¤#¦^§v �¤#³ ¬ § ® ���������0��%�� �j���E��q

�TWN�8�� ?�(*� �5@� �R��+,�q _)q*_o���"9�(*@{���(*���5DE;+�.P �(3�w�Gq���T±»Á$ª ® «d±#«>¯ y ´d±�§t¤@§�(�Á;¦>³R¤vªv« ¬ ��� � /!&����������WN���EdAq�TWN��U � � �*�� x#T�T�$%$7��_-q ��qL��4.@�LDE���&PA�8 v%$�ky}qL�A� � D2D:���K(9�$� �3qL,5q � ��(*�OB�t�� �RD����$� �3qL,�qL��Hh"&rE�K(3���y!qL� ��(*� �5@� �R��N,zq _)q ÄT¤@§s³ ¬ �

4��7� :"$�3@+1�D:�T?+�.�A�8 ���"$�h(S��h �� ��!"&rk�$���e���3D:�T(��w�`�{"�EDv�!���"9�A(*@{�(3#$th"&�!���Gq��d³R¯³{���������j��$���%��|��Ul&d�� �G�9q�TWN�8d� _a(* vc{���*q&B��(3 �1�;��T��%Kr:"& N�& E@�%�D�;�(�D�1*"&�hP+(8D�y�#T�*;�*�T�!�* R� *q r ªv¨[¤#¦Rªv¤3��� � ���$10 $��d����E�Aq�TWN�8�� Hh������� x7"&�� �}q ��qB �«>£}¯�«d¦R¤�§ ® ¤v£|³|¹;Á�³>¦d²M§ ® ¤´d£B³R¨l¦s� � ª ¬ ¨l¦R¨[ª#³ ¬ ¹T¤v£B±t¹T¤vª@§t¨l¥@¤«d¦�§ ® ¤£�« ¬ ¤«[©Q¤#±�§l£B«@Â$¤#¦A�&FG(* �D�;����"&�

FA@�P+#�� �;��T��%kg�<!��t �K"& E��GM\"9���"&� ��������q�TWN�8l� ]. :"�"0���!��'�� x�$4hqL� � E(*'�ABGqL���5(*t�(j��+,5q9FA :" ����1�D:� "0�$\"$r�yh# ��;�*�/�!�* x� I�j� 7�8(&��5�T��Dv;� �5��LD:�*�>BjDv(8DE�*\(*��5D�;����@$P# �T1

;��(3#LDE;K�T�K�(91�D�"&rk�$�*#�(S'�T��%K��� 7�8(&���"&���RD�q F � ���8���$l���U�WAq � ¯ ���¶>´ ¬ ¨µªP �¤#³ ¬ § ® � � � ������.�+���8����l$��U�WGq�TWN� � � Hh(*�`�{7"&�����q ��(9 :�T(8DE�T"9�`�T��7��cA�� :�*#T(8DE�*�C1*"&%��+� Dv�T?�!(SP�T# �LD:�2�6z(31* �"07�D�;+�K�!���{EDv E@(9#N1�'�13# �&qdU�£B³;¨l¦ �=¾�«�Â^¦ ��� �# � ����

���$W����U�+q�TWN�8X� Hh(*�`�{7"&�����q �NED� :"9%���{�� ��*#T(8D��8� ?0(9 :�T(8Dv��"0�$ �T� ;�@+�V(S� ��(�DE�T(3# (*��� (9 �DE�T1�@#T(8Dv"j v'���!"*D:"& ���� #T# *q

�T±»ÁJª ® «p¦R¤v¶>£�«>¤#¦+²R«>ªv£�¨l¦;« ¬ «@ÂvÁG��� � ��0����%��X�l$�������*q�TW�W�� FA;�� # #T�w�{���Bkq _-q �CB�;��� :t��T���]�q ]�q ��(3 :�T(�DE�T"&���T���!�S�!"& :'¡r�@�1�Dv� "&��(S���7��c�ED��� :"&� � ;"& :�!"0��6«(31* �"��aDv;�

�!���{EDE v@(3#+1�'�1*# �&q#�=±<Á$ª ® «d¦R¤v¶>£}«>¤#¦>²R«>ªv£}¨l¦R« ¬ «)ÂvÁG���# � ����� 07�0UX�l��Ed��$�Aq�TW�WN� � � "& :��"0�$��Heq ��qL��MN�*�*��Fbq y!qj<>"u���Tr�r:�� x����19�K�T�~13"0%���� D��T?�z�A�8 �r:"& ��V(S�019�`P{�RDvth�*���u�+;0(&R�*�"�rNDv;�`�!���{vDE E@(9#�1*'�13# �&q

�T±»ÁJª ® «p¦R¤v¶>£�«>¤#¦+²R«>ªv£�¨l¦;« ¬ «@ÂvÁG��� � ��0�������d&W|�8�E���*q

HA

L author manuscript inserm

-00243083, version 1

Å �

�TW�W�W � FA;�� # #T�w�{�� �!qL�|B�T#T?+�8 ��K(*�����q��`�TrEr:�� R���13�*��/�}Dv;�` R�8#T(8Dv� "&�R;+���m"&r.�!���{vDE E@(9#�1�'13# �z�+;0(&R��DE"~x�(8DE�T(9#G�A�� :rE"& ��V(S�13�"&��D�th"���(*��5D�;� R�*�6�v���T�!���{R�2"&��(3#&DE(j��*qB �«>£}¯"U�¤ ® ³>¥j���# � �!��/ *$0���8��l��El�d�q

�TW�W�� ���jDE�w��%�$M�q �!qL� ��?�� ��V(S��3��q Heq0B�7c{�E����R�LD��T?�\DE(j��\�T�K�!���K(*�+��th"0�!���kg&(hR��(3 �1�;VrE"& ���� :r�"& :�K(*��19�YrE#w@A1�D�@(�DE�T"&�(31* �"07�D�;����!���EDv E@(9#1�'�13#2�jq}U�¤ ® ³>¥��Q¤v¶>£�«d±Hªv¨���� � ��+������$����8�$�&U���8lAq

�TW�W�U � Hh(*@A��V(S�����_-qL�\B+#T(�P�P���"&"& ��$� �!qL� ��(*� � "$"��3����\B�q H�q ��,."9;���{���`�RD D:���+�/7��Fbq f�qL� � @��3D�@ v�&@��� �Kq�B+��cC;"& ��!"&��*(3rErE�*1�DN��+(8DE�T(3#$(*P�T#T�LD:� �*\�9@ :�/��%�Dp;���!���{EDE v@(3#+1�'�1*# �jq}U�¤ ® ³;¥�� ¤v¶>£}«d±Hªv¨������������/���+����W�Ud$�Ed��Aq

�TW�Wd� _a(S�0� ��Fbq _)qL�.4��T1�;$���3q ]�qL�.4�"�R���&P(*@+�}��4`q�BGq\���`�# �T13�LD}�!���!"& :'«?0(9 :�T�*�(31* �"07KD�;�C�!���{vDE E@(9#51�'019# ��g.�*EDE �"3%+�*��*rEr:�*1�D:\�w�K'�"9@�$%Kth"&�!���Gq��Q¤v¶>£�« ¹=±»Á$ª ® « ¬ «)Â$¨l³{�������������j�$d�� �j��WX�q

�TW�W�� FG"&# "�����(9�3DE"�#T(j��Fbq ��F�"j �DE�w���4hq � ��"����T�+���$��f�qL�GF�"&# "�� �KqL���� �R(3#T(j� �VqL���N v�j��"�#T(&��4hqA,.#T�T�K(31�D��� :�T1e�'��`�jD:"0�}`��"^�"*D�T�`�(3�T N1*"&%$��LDE�T?�I�{�� :r�"j ��K(*��13�*.�/�h�"�EDv�!���"9�(S@{��&q��"³^§l¶d£�¨»§ ³>±6��� � /!&��$106��������W�Aq

�TW�Wl� �`(3rEr:�*� �!qL� � �(3�9'� �!qL�+FG :�*���V(S��+y!qL�A,\@+�K�!�T��%���Bkq+B+�8 v@�¡�6EDv :"&%����# ��?�*#�7�+13"&%&��LD��T?���{�� :r�"& :�K(*�+13�*�+(*��K ��/��"&rk19"&%����LD:�/?�)���*1*# �/��5���!"$#��$�8 N19"&�K�K@+��LD�'Kth"&�!��� � ��*�519"&�K�e���3D:*q�� � � ¯ �/(¤v£}¨l³^§l£ � r «+ª��/� � � �������3� �G�8����W|�3q

�TW�W � � ].(3 E ��xD D��E,."&���+"j R�>��qL� � "j"$�&�V(S�{� � v@���� �>qV,I"&%���LDE�/?��r�@���1�D:�2"&��(*������+��"&%���"9@{«��7c�;+"j ��!"&�+�6«�T��"�#2���8 th"&�!���Gq�� � � ¯ � (¤v£}¨l³^§l£ � r «+ª��/� � � � ���10*����W �jX$�EX��+q

�TW�WX� ,.(* �#/�"&��.M�q ��q ��B�;��8 �th�w��.]�q ]�q�Hh�T%�;�� K# ��?�*# �"&rz�#T(j��!(m�6vDE :(9�j�T"�#�(*��CDE�*ED:"�ED��� :"&��C�T�o;�8(&#LD�;�')�*# �$�8 �#T'O�!�*�1*"&�K�(9 :�*�zth�LDE;K(*%�*���K(8Dv1*;�*�`th"0�!���K�V(9'`� :"*DE�*1�D�(&����1�D:\"&rk�7c��A# �T13�LD��!���!"� �'Gq5� ¤#¦R« ¹.³R¶p±H¤3�����������06����� �j�El�l+q

�TW���� �`(3rEr:�*� �!qL�NM�@+�/�|M.q �eqL� � :(3�9'� �!qL�N,\(*@#T��'� �3qL� �5 E(*�!�� x� �3qL�N,Z@��K�!�T��%��IBkq 4hqG,I"3%$�0�LD��T?������13# �/��!�T�mt`"&�!���a�T� :��#T(8DE� "0��DE"z�"&�A�2� :"*D��8�T�A�2P"9@��K"$�6EDv :(3�&� "&#>1*"&�13���3DE �(8DE�T"&�A*q 39³+¦Rªv¤@§ �����������/ �%��S�+l&� �j����W�q

�TW��� � ��"�#Tr:� �}q f�q � ���T :R1�;&P(*@+�!��,�q����0�$"&%���"9@{��*EDE �(3�&� "�#�(*��CD:�*EDE"�ED��� :"&��C# ��?�*# >(3 ��u(j7R"&13�T(8DE�*�ot��LDE;O13"&%$��LDE�T?���� :r:"& ��K(*��13�5�T�K"�# ���� �th"0�!���V(S��`�!���Gq  �«+£�¯"U�¤ ® ³>¥j�����������/�&�&Wd$X��E���Aq

HA

L author manuscript inserm

-00243083, version 1

Å �

� ����� ¢ � ª � ������������� ¦� A© � � ¦��� ������� ¢��A¢3§��:¦�§�� � � ¢ ����� ¦$§*¨ � �� � ¦���� � ©R¢�¦�����¢� {© � § ������� £ ��� ¢

"!$#�%'&�#�(*),+-%'.�+�(�/�0

132�4,5�6�7�4�7'8�9 À �-:�� ¿ � ¿ � "!$#�%'&�#�(*;�<=#�0>/�0 ? 5�8�8A@�7�B�8�2'C D�B-E�9'2�8

F�G,@�H�8�B-E�9'28AIJ (=KL+-.�/'MN%'&�#�O�P�Q-P'O�/ R 9'S�TUE�CUB-2V8 W=C>5�8�@�6X9'C>2�E�@ZY�9

F�8�2E�9\[-]�2^T_9'I` 97'C>9�E�5�CX4

� �/)$ � a *$b � ��������� ���%0��#.cd2�G�[�T>5�S�eR�}¸@¸ Àf ¿ � ��g

Å � ` [�2'E�@�2V8�hji�@�8�@ZEk4139'H�B$7�E�@ZY�9lC>9'2^T_5�S�@kS�mno9'C�i�2�8�6X8�B�9S�7�4hoCUE�@A7pB$8k2E�@�5VSR 2'S�B$28=TU[�9'9'H�qr7'5�5�C>H-@�S-2EA@�5�SW=9C>7'9�[-E�B�2V8�TU[�9'9'H

↑↑↓↓↓s

↓↓↑↑↑sut

↑ vZwyx>zU{j|k}_~�|�~ �cd2�G�[�T>5�S�eR�}¸@¸ Àf ¿ ��¸�g

� À ` [�2'E�@�2V8�hji�@�8�@ZEk4139'H�B$7�E�@ZY�9lC>9'2^T_5�S�@kS�mno9'C�i�2�8�6X8�B�9S�7�4hoCUE�@A7pB$8k2E�@�5VSR 2'S�B$28=TU[�9'9'H�qr7'5�5�C>H-@�S-2EA@�5�SW=9C>7'9�[-E�B�2V8�TU[�9'9'H

↑ss↓↓s

↓ss↑↑s

W=]�@k8�8k@�[�T�� ` ]�9�CU�o@kS�eR�}¸@¸ ¿f ¿)¿@À g

¿ � hlE�E�9'S�E�@�5�Sno9'C�i�2�8�G,9'G,5�C�4,F�D�5�S�m�2'S-H` ]�5�C�E�E�9CXG,I` ]�5�C�E�E�9CXG�no@�T�B$2'8�G,9'G*5�C�4D�5�S�m"E�9C>G�no@�T�B-2V8�G,9G,5VC�4

sss↓

sss↑� 5�C>H-5�S,��D�9'9Ve$�B¸@¸ Ã

f ¿)¿ �pgÃ�Å no9'C�i�5-T�9'��B$9'S�E�@k2�8�7'5�G�[�5-T>@�E�9

� ���'���V�U���������������V���-����������-�-�������A���N�� -����$��'��¡Z¡¢ ��������'� ¢ ����\�����-�-���V�������N£no@�TUB�5-TU[�2'E�@�2'8�7'5�G�[$5-T>@�E�9� ��¤ ��� ��¤ �¥������'������V¦£

s

s

s

s

s

s

W=]�@k8�8k@�[�T�� ` @�8ZY�9'CUG,2'S�eR��¸)¸��f ¿)¿@¿ g

� À no@�TUB�5-TU[�2'E�@�2'8�2i�@�8�@ZEk4r§¿ 1¨[-C>5�79VT�T>@�S�mà 1¨[-C>5�79VT�T>@�S�m

s↑

s↓©�[�EA@kS�m��«ªjY�9'C>G�2'SM�B¸)¸ �

f ¿)¿XÃ g¿ � no@�TUB�5-TU[�2'E�@�2'8�2i�@�8�@ZEk4,F ¿ 13I

no@�TUB�5-TU[�2'E�@�2'8�G,9'G,5�C�4R 5�E�5�C�H�9'¬�E�9'CU@�E�4

sss

sss

cd2BLT_G,2'S�S,9�E�2'8�e ¿)ÀvÀ@Àf ¿)¿@Å g

� ¿ no@�TUB�5-TU[�2'E�@�2'8�2i�@�8�@ZEk4��­3�'���k�-�����-�������A���N£ ↑ ↓

R 2'®�@$9pEL2�8Ae ¿vÀ)À@¿f ¿)¿ ��g

� � no9'C�i�2�8�[-CU@kG,@�S�m` [�2'E�@�2V8�[-CU@AG�@�S$m` [�2'E�@�2V8�T�4�S�EA]�9VT_@�T�Z­3��$���-�����-�k�����k����£

R 5�E�5�C�T�®$@�8k8? 8�B�9'S�7N4¯ B�9'HoY�9'C�i�2�8$C>97'2V8�8

↑↑

↓↓s

↑↓↓

↑↑s

↑@�G"[-C>5'Y�9'H�7V5�m�S�@kE�@ZY�9j[�9'CU6X5�C>G,2'S�7'9�TNe

↓H-9'7C>9'2^T_9'H�7'5�m-S�@�EA@ZY�9j[�9'CU6X5�C>G,2S$79VTNe s S�5oG,5�H�@k6U@A72'E�@�5�S�°'©�±�§�9VTUE�C>2'H-@�5�8U°�W=m=§[-C>5�m�9VTUE�9'CU5�S�9�°

ªjY�§�5VY�B�8�2'E�@�5VS ·

²u³

´3µ

¶�·

� Å

HA

L author manuscript inserm

-00243083, version 1

��

����� ��� � � ��� ������������������������� ���� ��� �������� �������� ����� ��� ����������� ��� ������ �� ����� ����� ������������ ���������

��� !�"#$%�&"��!'�"�$( ) ↓

* �%+& $�),$!"!*& & %#(& !$)-. /�0( �!$�)-1 /�0( �#*& !+ )$�2 -1 /$!$3��!( �& $32 !4$* �0( �#*& !+ )2 -1 /2& !#'#&+ #2+ ��0( �#*& !+ )5 6/��!6�0( ��!$�)7 /( �0( !0( ��!$�)( !(7 /( !( #+ ( �0( !0( ��!$�)

$�2 7 $!$3��!( �& $32 !4$* ( �0( !0( ��!$�)8 $* �0( /#$* �!0( �$�*& !$�)9:;< /0�=> !�"!$�2& $*& $66+ !2 4+& $)? "@AA9- /? "!*& & �* @"& $& 3"�$( #+ 0( #( 40�=#"& $#(& !$)B7 /B �#%(& !$7& "�)7A78?;@ /7 �#&+ 3A#C& $6

7 �0( �#�(8? !�;@ );AD /2 !* E"#00& $* �=)$0/$!( 0��%& & �* )9-9 /0!%&! 3�%!$!"& %0( #( 40GF

H I JK L

H JMN OPI QRSK

T UVV UWJX?YZ@

[ \O^] _`abcd

H OSQe Ie fe I L

? �6g "+@

H Ohe PPUSPOSI hRIe US

A �#$i "& $3"#=j? �6g "+@

k U\Se Ie fOOfRV JRIe US

l JIPUmOQ

n opq borrs ptu ob

at`wv`x yzaqs op v

5 !+ !3{ #$( !+ #

.||}

i11~j

~~ > E0( ���%( !"& ��*

$!%4���$( 40��0

$!YZ

�~ F�$0

-1� F~i. F� 3.� F�j

9& "�+ �#$* %>!& %�B7�� !$( �!++ �* ��!%�00& $6G�

8 (( �$(& !$? '& 04#+i9 ( �!!�j #$* #4*& ( !�E@ F

,?-1@ F

�"�+ !E"�$( �

9-9 �0( ��00 �

#(& 64� �?* ����00&!$ �

'#0!"!( !�

0E"�( !"0@

� # � �.||�

i11}j

��1 $!%4���$( 40��0

� E�YZ

}. F|

-. /$0 -1 /�

-. /11 F�i�3}~j

-1 /~ F�i�31�j

5 0E%> !"!( !���� !�"#$%�����%��( 4#+

!�6#$& �#(& !$g #(( �$(& !$ F

�& 04!"!( !�( �#%C& $6g #(( �$(& !$i7A7;j F

"AA9- F

#(�#$* � E�?>& 6> -.@ ),#(� #$* � E�?-1@ F

,#(� #$* ↓

#(� E�?>& 6> -.@ ),#(� #$* � E�?-1@ F

,#(� #$* � E�?-. �-1@ F

* ����00& !$ �

0( �!C �

#+ %!> !+ #$*

��& 6> (

; #���(( 3� !$$!� �

.||| i11�j

�|� $!%4���$( 40��0

$!YZ

}�

-. /� ( !(-1 /�2 -1 /� ( !(

7 /1� F1

2 7 /1� F1

-. /.� F�i $0j

( !(-1 /� F�i $0j

2 -1 /�i $0j

( !(7 /.}�i $0j

2 7 /�|i $0j

� �+ #E�* '& 04#+ ��%#++ F

AA9- F� ������/D ""�*& #( �'& 04#+ ��%#++ �Y+ 4�$%E �& ""�*& #( �

#$** �+ #E�* '��2 #+"�"!�E �7A7; F

?+ !�-1@ F

?>& 6> ( !(7 �>& 6>27@ F

,?-. �( !(-1 �2 -1 �7@ F

?* ����00&!$@

� #�+ 0!$ �1���

i11|j

�� .�%4���$( 40��0

. F� E�YZ

}1 F.

-1 /� F1

Y ���7 /� F.�

-1�.�i $03.1�j

Y ���7 /$0

Y+ 4�$%Eg9 �"#$(& %"�"!�EG�� �+ #E�* '��2 #+"�"!�E F

� �������D""�*& #( �'��2 #+"�"!�E �D ""�*& #( �#$*

* �+ #E�* '& 04#+"�"!�E �#(( �$(& !$#$* %!$%�$( �#(& !$ F

↑#(�$!( #(. F� E�?>& 6> 7@ ),#(� #$* . F� E�?-1@

,#(� #$* . F� E�?-1 �7@ F

9-9

� �#C � �1���

i|~j

�|�1.�#0( ��%4���$(

#$* .| $�'��

40��0

$!YZ

}|

����#$6�*

�!"�( !���6g"+ �

-. /�� F|i.13��|j

( !(-1 /.�F~

i�3~�j

2 -1 /�F1

i. 3..j

5 6/.��i�� 31��j

7 /1.1i��3|�.j

8 $* �0( /���i|3�1�j

� �+ #E�* '��2 #+"�"!�E#$* ��( �& �'#+ � & %& �$%E F

D ""�*& #( ��* �+ #E�* '& 04!0�#(& #+ "�"!�E F

Y+ 4�$%E F� ������/'��2 #+ #(( �$(& !$ �0�"#$(& %"�"!�E �7A78

#$* ; �AA9- F

?>& 6>2-1@ F

?>& 6> ( !(-1 �>& 6>2-1@ )

?>& 6> -.@ F

?>& 6> 7@ F

,?-. �( !(-1 �2 -1 �7 �5 6 �8 $* �0(@ F

-B7 40� �* ����00& !$

��#%(& %�

� �%(

� # � �1���

i1��j

�1� ~.%4���$( 40��0

~E�YZ

}. F�$�2 -1 /� F.

2 -1 /$0( !(7 /� F~�

$�2 7 /.�

$�2 -1 /� F.�i� F��3. F1�j

2 -1 /. F�i� F.�3.� F~j

( !(7 /11�i� 3�~� F�j

$�2 7 /1 F��i�3.. F~j

"AA9- F

,#(� #$* ↑

#(~E�?>& 6> $�2 -1 �>& 6>2-1@ )

,#(� #$* ~E�? ( !(7 �$�2 7@ F

;AD �

04�6&%#+

"�$!�#40� �

-B7 40� �2 #0�+& $� "AA

9-

� !+ �1��1

i1�.j

��

$!%4���$( 40��0

$!YZ

~�

-1 /�

( !(7 /��

-1 /.1 F.i� 3��j

����� �¡�¢ �� £¤ ¥¦§

7 /�}�i $0j

- �& 0!*&%'��2 #+"�"!�E F

� ������/Y+ 4�$%E �9 ( �!!�& $( �� ���$%� �9 �#(& #+

"�"!�E �A �$( #+ �!( #(& !$ F

?>& 6> -1@ ) ↑

?>& 6> ( !(7@ F

,?-1 �( !(7@ F

333

: !6��'!�0( �

1���

i.}1j

~~ $!%4���$( 40��0

$!YZ

}� F~

( !(-1 /� F�

( !(7 /�|

( !(-1 /~ F}i. F. 31� F�j

( !(7 /.}�i� 3..|�@

� ��2 #++& 0( ��%#++ F

� ������/� ��2 #+�#& ��* #00!%& #( �0 �9 �"#$(& %'��2 #+

"�"!�E ��& 04!0�#(& #+ "�"!�E F

?>& 6> ( !(-1@ � ↓

?>& 6> ( !(7@ F

,? ( !(-1@ F

* ����00& !$ �

;AD �9:;< �

0"!C& $6#$*

#+ %!> !+ 40� F

HA

L author manuscript inserm

-00243083, version 1