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Missing data in randomized controlled trials of rheumatoid arthritis with radiographic outcomes: A simulation study.

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(1)Missing data in randomized controlled trials of rheumatoid arthritis with radiographic outcomes: A simulation study. Gabriel Baron, Philippe Ravaud, Adeline Samson, Bruno Giraudeau. To cite this version: Gabriel Baron, Philippe Ravaud, Adeline Samson, Bruno Giraudeau. Missing data in randomized controlled trials of rheumatoid arthritis with radiographic outcomes: A simulation study.. Arthritis and Rheumatism, Wiley, 2008, 59 (1), pp.25-31. �10.1002/art.23253�. �inserm-00217436�. HAL Id: inserm-00217436 https://www.hal.inserm.fr/inserm-00217436 Submitted on 7 Sep 2011. HAL is a multi-disciplinary open access archive for the deposit and dissemination of scientific research documents, whether they are published 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..

(2) HAL author manuscript.  

(3)   !!"$#%'&()*)"$+",')-./".01)2)3!#4,"  Arthritis and Rheumatism 2008;59(1):25-31.  52!678:9;724 ".< =!2*>"$38*)" #4) ?@#A3,8" AB3CED HAL author manuscript. FHGJILKNMBOQPSR6TUVWYX[Z8\B]EUQW'^`_badcfe+gBXh\[XjiBikZmlUSnkUobpqadc`rpBZ8\[Xs_BZ!tkU8uwv'^B_fx'cf]$Wyok_B^ T<XzW'UobpBZ8Uok{. inserm-00217436, version 1. da TUVBW'X[Z8\]USW'^B_Bc`|}tk~8c`e)gBX[\sXhiBikZ<lUSnkUobpBcB|€c`eg5‚Bƒd„ tf†‡l |/c`ˆH‰BŠ‹Œc`eUSW'Xsv'cŽ6WLU_~8Zffˆ€_BX‘nbZSWv'X“’•” eUSW'Xsv‡‰? Z8_BXdv+€X[pBZSW'^f’–cfˆŽql—pBZ |/”pBZ8~8Xj_kZceUSW'Xdv'c`ŽJW'US_B~5Zkr e˜š™ec™H›`iBXœ’•U\f]X[~gkU’•cH”SikUSWd’•ZSu€Z8_’ pq‘†(ikXhpB”8u:Xh^k\h^`žkX[Z8cf]EXh^qvy’•U’–X[vy’•XhŸobZEZ’6lZ8~SgBZQW'~8gBZE m\[Xh_BXdŸobZ8cfeUSW¡XsvLcŽ6WLU_~8Z x¡rpBZ8\sXh_kZ%tkUuwvL^`_c¢egHc¢ˆ?|£l  )„HlCt‹6¤¥q¦Œcw§.UVk^BW'U’š^`X‘WLZ¨pBZ©|/U’–g”8u:U’–XhŸo6Z5vªrEiBik\sX[Ÿob”8ZvLc ˆC_BX«nbZQWv'X“’•”meUSW'Xdv(¦ŒceUSW•Xsv'cfŽ6W'U8_B~Z {y]$Wyok_^©T?X‘WLUobpBZ8Uobc eg¢mƒd„‚t†‡l |/c (ƒ' ­¬k®f¬kc¯)^fokWv'cmŽ6WLUS_B~5Z? .™Clmˆ°pBZ¯±^fokWvLc? (ƒ' ²¬k®f¬Bc ¯‡^oWv'cfŽ6W'US_~8Z FH³N³6OQ´5PP(µ8MkO8OQ´5P¶6MB·6³N´·Nµ´E¸B·N³‚OQ´8¶6OS¹[·JI‡O´8º6GN´PYI'P±ILM TUVBW'X[Z8\m]USW'^B_Bc±H”SikUSWy’•ZSuHZ_5’Cp» †.iX«pB”u Xh^\h^BžkXsZw]EXd^qvd’•U ’–Xdv–’¡XhŸobZ¼Z’ElZ8~8gBZSW'~8gZ½  \sXh_kXsŸobZcmTEW'^fokikZ ™H^Jv•iBX“’•U8\jX[ZSW+]X[~gU’•˜¡  \hUobpBZm]ZSW'_BUSWLpBc`¥k¾!WyobZm™HZS_fW'Xf™ob~SgBUQW'pBc‰¦Œ®+¤8‹EeUSW¡X[v'cfŽ6W'U8_B~8ZŒ¿ ¯‡Z\šÀŠBŠÁ®+¤ ¥k®!¬q¦‰B€ŠB ŽUSÁ5À+ŠBŠ€®+¤ ¥k®!¬q¦C¾B‰!‰BŠ †,˜yu€U8Xs\•žkUSVBW'XhZ8\–¿ÄV`USW'^B_kÅÆV`~8gq¿œUSiBgfi6¿œÇdW È MBOQ³ µ8MBG6·qIR6Šf¥k‰BŠ.

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(5) ´8µSI'¹b´+¯)gBZ€ifokW¡ik^JvLZ:^BDZ’–gBXdv?v–’dobpHUfvm’š^. HAL author manuscript inserm-00217436, version 1. U vvLZv7vm’–gZ:Xsu€ikU8~’•c+Xh_w’•ZSW'u:v^Ç vy’•U’–Xšv–’–X[~8U\ ik^€ZSW.US_pÁVkXsU5v ^BÇ+’–W'Z8U’–u€Z8_’‡Z8ǖǡZ~’•cq^BÇ)USiBiBW'^kU8~SgZfv±’–^wpBZUS\hXj_BžHX“’¡g u:Xdvv'Xh_fž‚pBU’•UXj_€W'U8_pB^u€XZp ~8^B_’–W•^`\h\[Z8p?’–W¡XhU8\dv‡^BÇ6W¡gkZobu:U’•^`Xhp€USW–’–gfW¡X“’•XsvHX“’¡gCW'U8pBXh^`žBWLUSiBgBX[~E^oŒ’•~S^Bu Zv¿  ´SI'K6MB³6P‚r v'Xsu!ob\[U’¡X«^`_-vy’dobp€Ufv/ikZSW'ǖ^BWYuHZ8pq¿‚¯ gZu€Xdvv'Xh_Bž_Zfvv—u Z8~8gBU8_BXdv'uwv  Z Xh_fnbZfvy’–X‘žkU’•Zp ~^`iBX[Z8p¨’–gBZ©iBWL^~8Z5vv/^BÇ!€X“’–gBpfWL"U €U8\ ÇdWL^u ’–W¡X[U8\šv1pobZ ’•^\«U$~ #4^BÇ£Z8ÇyÇ¡X[~5U8%~ b'¿ & Z ~8^Bu!ikUSW'ZpÁ’–gfW'Z8Z!u Z’–g^pv,^`LJu U_USžkXj_Bž‚u:Xdvv'Xh_Bž‚pBU’•UB) (¡X * U8\h\+USnbU8Xh\[UVk\[Z€pBU’•+U (•~8Uv'ZC~8^u!ik\[Z’•%Z *',c (yXhX * \[Ufvy’£^fVqvLZSW¡nkU’•Xh^B_%~8USW¡W'X[Z8p%ǖ^`-W HUSW' p (š/§ . ±,Ž */U8_B p (¡XsX[X *>u!ob\“’•Xjik\[Z X[u€ifoB’•U’–Xh^B_q¿!€U’•0 U HZSW'Z ’–gZS_ US_U\12ŒZ8p¢2V ¼~8\[Uvv'X[~8U8\N’•˜s’•Zv–/’ (¡~S^Bu!ikUSW'Xh_Bžw’–gBZÁu Z8U8_¼UV6v'^k\“oB’•Z€~SgBU8_fžkZ!VkZ3’ HZ8ZS_wVbUvLZ\[Xh_kZÁU8_p Ç¡Xh_kU\ nkXdv'X“4’ * ^BW±Ž ’•Zvd/’ (¡Z5vš’–Xhu U’•Xh^B_w^BÇ+’–W'Z8U’–u€Z8_5’.ZSÇyǕZ8~5’ HX“’–gwW'ZSikZ8U’•Z8p:u€Z8UfvyokWLZu Z8_’'v‡2V ‚U!\hXh_kZUQWmu€X‘ÃbZ8pB˜ Z8ÇyǕZ8~’'v‡u€^kpBZ8\ *¿ C´8P7G 6hI7P 8&}X“’¡g u:Xdvv'Xh_BžwpBU’•UEW'U’•Z~S\h^qv'Z ’–^ ¤8:¦ 9¼cf’–gBZ<’–W'ZU ’–u€Z8_5’‡Z8ÇyǖZ5~;’ €U5v ok_pBZSW'Zfvy’•Xhu U’•Z8p V2¤8:‹ 9 Uv,Zvy’•Xhu U’•Z8p:2V ‚U!\sXh_kZ8USW u X«ÃbZpB˜¡Z8ÇyǕZ5~’'v u€^kpBZ)\ €X“’•g‚UHu!ob\“’•X‘i\[Z€Xju€ifoB’•U’–X«^`_‚USiBiBWL^U8~QgÁ’•^ u:Xdvv'Xh_BžwpBU’•Uf¿B¯)gBXsv±VkX[Uf5v €Ufv(\«^ HZSW)’–gBU8_!’–gBU’ ^VŒ’•USXh_kZ8 p €Xœ’–gH’–gZ!~8UvLZ8˜¡~8^ku!i\[Z’•<Z (¡˜y¬q:¦ 9=*‡^`W)/§ .? ±Ž (¡˜¡Š:¦ 9=*(USiBiBW•^kU8~SgBZ5v¿B¯)gBXdvEvy’•U’–Xsv–’¡X«~8U8\+UQiBiBW'^U~S g (¡~8^u!VkXh_kU’•Xh^`_ ^Ç)u!ob\“’•Xjik\[Z!Xju€ifoB’•U’–X«^`_ U_p:u:X‘ÃbZ8pB˜ Z8ÇyǕZ8~’'v¢US_BU8\ bvXd>v *€Uv‚u€^BW'Z8^fnkZQW‚Uvv'^k~8XhU’•Z8p €X“’–g U‰B® 9 ik^ €ZQW (yǖ^BW‚UÂB® 9 _B^Bu€Xj_kU8\!\[ZSnkZ8\ *Lc CgBZSW'ZUv /§ . ,? Ž HUvUvv'^k~8XhU’•Z8p €X“’–g¼UÁik^ €ZSW,^`Ç ¦B:¦ 9 US_Bp¼~8Uv'Z ~8^Bu!i\[Z’•Z UÁik^ €ZQW ^`Ç$¦B:‹ 9¿6¯)˜ ’•Zvd’CUS_U1\ qv'Xdv€žbUn`Z ŸobU8\sX“’•U’¡X‘nkZ81\  Z8ŸoqX‘nbU8\[Z8_’EVfoB’ik^k^BW'ZWHŸobU\hX“4’ WLZv–oq\œ’'v'c ZSÃk~8ZSif@’ HgBZ8_u!oq\“’•Xhi\[Z Xsu€ifoB’•U’–X«^`_ HUv‡UQiBi\hX[Z5pq¿ MB·6%µ 6[GNP7¹sMB,· . okWÁv'X[u!oq\[U’–Xh^B_>v–’dobp Æv'gB^ €Z8p u!ob\“’•Xjik\hZ X[u€ifoB’•U’–Xh^B_ ^kÇyǖZSW'Xh_Bž½’–gZ½v'u U8\j\[Zfvy’ VkX[Ufv Xh_>’–WLZ8U’–u€Z8_’ Z8ǖǡZ8~’wUQ_Bp>’–gBZgBXhžgZvy’ ik^ €ZSW ¿(¯)gBZvLZ W'Zfvyob\“’'v‚~8U8_—gBZ8\hi©Xh_—i\[U8_B_BXh_Bžª’–W¡XhU8\dv7c Zv•ikZ8~8XsU8\[\ €Xh_ ~8gB^k^Jv•Xj_Œž:u Z’–g^pv‡^BÇ+Xhu€ifoB’•U’–Xh^B_€US_p:pBU’•UEUQ_BU8\ qv'Xdv¿.

(6) ´ €MBOQ³6PSR)W¡gZoqu U’•^BXhp‚USWy’–gŒWYXœ’¡XsvLcNW'UQ_BpB^u€X1ŒZ8p ’–W•XhU8\švLc v'X[uHob\[U’•Xh^`_ v–’dobpc6W'U8pBXh^`žBWLUSiBgBX[~Á^foB’•~Q^`u€Zc  u:Xdvv'Xh_Bž pBU’•U . HAL author manuscript inserm-00217436, version 1.

(7) HAL author manuscript inserm-00217436, version 1. l$gkZobu:U’–^BXhpªUSWy’–gŒW'X“’¡X[v(šlr@*:Xdv€’–gBZ½uH^Jv–’€~8^kuÁuH^_ª~QgfW'^B_BX[~½Xh_Ǖ\sU8u u:U’•^fW-L^Xh_’Hp`Xdv'Z5UvLZ U8_Bp/Xyv W'Zv•ik^`_kv'X‘Vq\[Z¨Ç–^BW v u€if’•^`u€U’¡Xh~ u:U8_BXhǕZv–’•U’–Xh^B_v (¡Zf¿œž6¿œc Çsoq_~’–Xh^B_kU8\ vy’•U’do6vLc ikUSXh_ * US_pvy’–Wyob~’dokW'US\ pBU8u€USžkZ (LX ¿“ZŒ¿“cEpBU8u€UQžkZ ^Ç?’–gZ USW–’–Xh~ob\sUQWw~8USW–’–Xj\[USžkZ£U8_Bp>Vk^B_B%Z * (S¤ *¿)†(ǖǡZ~’¡X‘n`Z pBXšvLZ8Ufv'Z8˜¡u€^kpBXj4Ç kXj_Bž US_5’¡Xh˜–W¡gBZobu U’•Xh~>pfW–okžqv USW'Z/Xj_~SW'Z8Ufv'Xh_Bžk\ ;USnkU8Xs\[USVk\[ZªUvw’–gBZSWLUS8i 0(y2¬ *¿ r€vvLZv7v'Xh_Bž¨vyoJ~8gª’–W'Z8U’–u€Z8_’'v W'Z8ŸobX‘W'Z5v<’–gZ u:ZUvyokW'Z8u Z8_’<^`Ç!v–’–Wyob~’doBWLUS\ ^foB’•~S^Bu€Zv€Xh_ WLUS_BpB^u€1X ŒZ8p ~^`_5’–W'^`\h\[Z8p ’–W¡X[U\dv (šl< m¯(v *E’–^ pBZ8u€^B_qvy’–W'U’•Z U W'Z’•USW'pBU’–Xh^B_^BÇp`XdvLZ8Ufv'Z iBW'^BžBW'Zv7v'Xh^B_q¿+lU8p`X«^`žBW'UQiBgBXs~¼^oB’•~Q^`uHZv€USWLZ ^`Çs’•Z8_ o6v'Z8pUfv iBW'Xhu:UQW HZ8_Bpfik^Xh_5’'v)ǖ^`W‡U5vv'Z5vv'Xj_Bžwv–’–Wyob~ ’dokWLUS\qv'ZSnkZQWYXœ-’  (•ŠB˜¡¾ *¿ ]Z8~8Uo6v7Z WLZ’•USW'pBU’–Xh^B_—^Çwvy’–Wyob~’dokW'US\pBU8u USžkZ1Xh_—lE $¯,v W'Z8ŸobX‘W'Zv‚^fV6v'ZQWynbU’–Xh^B_—^fnbZSW:’–Xhu:Zc ǖ^\h\h8^ H˜šoki¼^`LJikU’•XhZ8_’'v$^BÇs’•Z8_ _Z8~8Zfvv'X“’•U’•Zv Xh_5’•ZSW'u:Zp`X[U’•Z?nkXdv'X“’'v'c6W'Z8ŸobX‘W'Xh_Bž u€^BW'Z?’–gBU8_:3’ €^ v'Zv7v'Xh^_qv ^BÇNWLU8p`X«^`žBW'UQiBg :Xh_€u€^Nv–’q’–W¡XhU8\dv (¡‰ * ¿tBikZ8~SXhÇ¡X[~Eu Z’–gB^kpv(vyob~Qg€Ufv±\hXh_kZ5USW‡uÁX‘ÃbZ8pB˜•ZÇ–Ç•Z8~’'v‡u€^kpBZ\dvLc CgBX[~g ZÃi\h^kX“’¨’–gZ W'X[~8gB_BZvvA^Ç@’–gBZ p _kU8u:X[~fvA^VŒ’•UXh_kZ8p €X“’•g vyob~8g \«^_fžkX“’dobpBXj_kU8\hc@^BW%W'ZSikZ8U’•Z8pBc u Z8UfvyokW'Z8u Z8_’'v ~8^fok\hp4VkZ%USiBik\sX[Z8p4’•^Z5vy’–Xhu U’•Z ’–gBZ¨’ W'Z8U’–u€Z8_5’—ZSǖǕZ8~’ (Y:‹ *¿w€Z5v¡iBX“’•Z W'ZSikZU’•Z8p u Z8UfvyokW'Z8u Z8_’'vLc(~8U8\h~ob\[U’¡Xh_Œž½’–gBZ u Z8U8_£~8gBU8_fžbZ¢VkZ3’ €Z8ZQ_ VkUvLZ\[Xh_kZ¼nkXdv'X“’<U8_BpZ8_Bp£^Çm’–gZ½vy’dobp ÆXs_ Z8U8~8g žBWL^okiAUS_p ~^`u!ikUQWYXh_Œž4X“’ 2V  ov'Z@^BÇ ’–gBZ@~8\[Uv7v'X[~8U8\¢’•˜s’•Zvy’ (y^BW½|1US_B_B-˜ &—gBX“’•_B%Z  ’•Z5vy’£Ç–^`W _B^B_fikUQW'U8u:Z’–WYX«~E~8^`uCikUSW'XšvL^`_q>v *)W'Z8u€U8Xh_qv+’–gBZ?v–’•US_BpBUSWLpÁUQ_BU8\ bvXdv¿ ¯)gBZ!Xh_’•Z8_’•Xh^B_B˜š’š^˜s’dW'ZU’ (yƒL¯)¯ *(iBW•Xj_~8Xjik\[Z!Xšv‡’–gBZ€~8^BW¡_BZQWvy’š^`_Z!^`Ç)l  ¯,v (¡ÂB˜S¤B¤ * U8_BpwXdv €X[pkZ8\  W'Z8~^`u€u Z8_BpBZ8p?’•^€pBZSu€^B_qvy’–W'U’•Z,’–gZ?vyokikZSW'Xh^BW¡X“4’ H^`Ç^B_kZm’dW'Z8U’–u€Z8_’^fnkZSW‡UQ_B^’–gBZQW (S¤¬kc+¤QŠ *¿S™C^ €Zn`ZSW'c Ǖ"Z ¨’–W•XhU8\sXdvy’'v‡o6v'Z<’–gBXdv(iBW'Xh_k~8Xhi\[Z!Xh_‚U_U8\ 25Xh_Bž:’–gBZ8X‘W,pU’•U (S¤¥Bc(¤8:¦ *•cJikUQWš’–Xh~oq\[USW'\ ‚Xh_:’–W¡XhU8\dv$Zn`U8\«obU’¡Xh_fž W'U8pBXh^BžBW'USiBgBX[~€^oŒ’•~S^Bu€Zfv$Xj_:lr (Q¤Q¾ *¿k¯ gZHƒL¯±¯iBW¡Xh_B~8Xhi\[Z!W'Z8ŸobX‘W'Z5v(’–gBU’,U8\j\6ikU’•XhZ8_’'vLc CgBZ’–gZSW(’–gBZ8X‘W pBU’•U X[v€~8^uCi\[Z’•Z ^BW!Xh_B~^u!ik\sZ’•Z8c±VkZ Xh_B~8\‘obpBZ8p1Xh_ ’–gZ½vy’•U’–Xdv–’¡Xh~U\$U8_BU81\ qv'Xdv¿‡rEiBiBW'^ÃkXhu U’•Z8\  3’ H^˜ ’–gBX‘W'pv^DZl  ¯(v^`Ç(lr gUSnkZwU:u:Xdvv'Xh_fž£pBU’•U€W'U’•Z€žfW'Z8U’•ZSW(’–gBUS_/¤Q® 9 ǖ^`W$W'U8pBXh^BžBW'USiBgBX[~:^foB’•~S^Bu€Zfv (S¤Q¾ *'cBUQ_Bp?’–W¡XhU8\hXdvy’'v‡u!o6vy’6o6v'Z u Z’–g^pv)ǖ^BW‡pBZ8US\hXh_B+ ž €X“’•g€uÁXdvv'Xh_Bž pBU’•U,’š^:USiBiB\ ’–gBZ ƒ'¯‡¯½iBW•Xj_~8Xjik\[Zf¿ ƒ¡_‚’–W¡XhU8\dv!Xh_fnk^\‘nbXh_Bž \h^_ŒžXœ’dobp`Xh_kU8\(u Z8Uv–okW'Z8u:Z8_5’'v^`ÇEWLU8p`X«^`žBW'UQiBgBXs~w^foB’•~Q^`u€Zc±u€Xšvv'Xh_Bž£pkU’•U ~8US_¼W'Zfvyob\“’EÇdW'^ku\[U8%~ #£^Ç$Z8ǖǡX[~U~ ½^`WU8pn`ZSWvLZ ZSnkZ8_5’'v'c±Ç–^BWZÃkU8u€ik\sZŒ¿ &—gBZ8_ pBU’•UwUSW'ZwXj_~8^u!ik\[Z’•Z8c.

(8) HAL author manuscript inserm-00217436, version 1. 'W Zv–oq\œ’'v‡^`Çq’–gZm’–WYX«U\b~8U8_!VkZEU8ǖǡZ5~’•Z8p€Xh_?’3€^€u€U '^BW€U%qv ¿ŽX‘Wvy’•cBu€Xšvv'Xh_Bž pBU’•UE~8UQ_!W'Zv–oq\“’Xh_:U VkX[Ufv‡^`Ç ’–W'Z8U’–u€Z8_’ ZÇ–Ç•Z8~’ Zv–’¡Xhu U’•Zv ¿ Ž^BW@ZÃ`Uu€ik\[Z8c ikU’•XhZ8_’'v;ZÃikZSW'X[Z_~8Xj_Bž žBW'Z8U’•ZSW;pBZ’•ZSW¡X«^`W'U’–Xh^`_ Xs_ vy’–W–ob~ ’dokW'UQ\‡pBUu USžkZwu %U  VkZw\[Zvv\j1X #kZ8\ ¼’•^½~^`u!ik\[Z’•ZH’–gZÁnkXdvX“’'v ¿Nƒ•Ç u:Xdvv'Xh_fž£pBU’•UwUQW'Z:X‘žk_B^BW'Z8p US_Bp US_U1\ qv7Zv1USW'Z©VkUvLZ8p%^`_%^B_B\  ’–gBZ@pBU’•U@^`Ç ikU’–XhZ8_f’'?v CgB^AUWLZ@pf^BXj_Œž €Z8\s\«c ’–gZ_ ’–gBZ@pBXšvLZ8Uv7Z iBW'^BžfW'Z5vv'Xh^B_ ~8^ok\«pÁVkZmob_BpBZSW'Z5vy’•Xju U’•Z'p (Q¤Q‰ *¿tkZ8~^`_pBc`u€Xdvv'Xh_Bž:pBU’•UE~8U8_!W'Zv–oq\“’Xh_:\h^qvv‡^Ç)vy’•U’–Xšv–’–X[~8U\ ik^ €ZS W (yXd¿œZf¿œc ’–gBZ¼UVkX[\sX“4’ /^BÇ ’–gkZ¢’–W¡X«U\(’•^/pBZ ’•Z~’CU pfXhÇyǕZSW'Z8_k~8Z V`Z3’ €ZZS_žBW'^fokiqv *!XhÇCpBU’•U ǖ^`W:vL^`u Z vyoBV 7Z5~’'v‡UQW'ZEZÃk~8\“obpkZ8p€ÇdW'^`u©’–gZEUS_kU8\ bv'Xšv (S¤Q‰ *¿ tkZn`ZSW'U8\±u Z’–g^pvZÃkXdvy’.’•^½Up yo6vy’$ǖ^BW u€Xdvv'Xj_Bž pBU’•U (S¤8:‹ * ¿™C^ HZnkZQW'c)~8^B_B~8\“ov'Xh^`_qv^DZ’–W•XhU8\yv (¡Xd¿œZf¿œc+vyokikZSW'Xh^BW¡X“4’  ^LJ^`_Z?’–W'Z8U’–u€Z8_’.^fnkZSW U8_^’–gZSW ^fW(_^’  * US_p ’–W'ZU ’–u€Z8_5’.ZÇ–Ç•Z8~’.u:%U wV`Z!U8Ç¡Ç¡Z~’•Z8p V2 ’–gZ u:Z’–gB^kp½o6v'Z8p½’•^gBUS_p`\[Z u:Xdvv'Xh_fž/pkU’•Uf¿ &}Z UXhu Z8p½’•^/~S^Bu!ikUSWLZ¢’–gBZ Xsu€ikU8~’C^`ÇpBXsǖǡZQW'Z8_’ USiBiBW'^kU8~SgZv.~8gB^qv'Z8_!’•^wpBZ8U88\ €Xœ’¡g u:Xdvv'Xh_BžwpBU’•U oq_pBZ8W(U!v'~8Z8_kUSW'Xh^Á’–gU’‡u€Xhu:X[~fv ’–W'XhU8\dv ^BÇ+lEr €X“’•gwU W'U8pBXh^BžBW'USiBgBX[~!^foB’•~S^Bu€Zf¿ & ZikZSW'ǖ^`W'u€Z8pwU:v'Xhu!oq\[U’•Xh^B_ vy’dobp b¿6tfob~g‚vy’dobpBXhZfv'c6Xj_~SW'Z8Ufv'Xh_Bžk\ ‚~^u€u€^_ Xh_¢’–gZÁu€Zp`X[~5U8\+\sXœ’•ZSW'U’dokW'Zc+USW'Z?o6vLZ8pÁ’–^ U5vv'Z5vv(’–gBZ!ikZSW•Ç–^`W'u€U8_B~ZÁ^kÇmv–’•U’–Xsvy’•Xh~8U8\)u Z’–g^pv$Xh_wW'Z8\sU’–Xh^_ ’–^©’–gBZ #k_B^ !_©’–W–oB’–g (S¤Q *¿ &}Z—~8^u!ikUQW'Z8p USiBiBWL^U8~QgBZfv ’•^¨gBU8_p`\[Z u Xdvv'Xj_Bž pBU’•U—Xj_@’•ZSW'u:vÆ^`Ç vy’•U’–Xdvy’•Xh~8U8\Bik^ €ZSW‡UQ_BpÁuHUSž_BXœ’dobpBZE^ÇqVkXsUfv‡Xh_’–W'^kpob~8Z8p 2V €u Xšvv'Xh_Bž pBU’•U$^`_?’ W'Z8U’–uHZ_5’ZSÇyǕZ8~’7¿.

(9)    .  

(10)       !" HAL author manuscript. &}Z?~8^B_v'X[pBZSWLZ8p€UHv'X[uHob\[U’–Xh^B_?’–W'XhU8\VkUfvLZ8p€^`_€U. inserm-00217436, version 1. k¬ ˜•USW'uwZ8p?l  ¯½W'ZvLZ8uHVb\sXh_Bž!lErª’–W'XhU8\dv€X“’•g€U~8^B_’–W•^`\ žBW'^foki US_Bp—U8_—ZSÃBikZSW'X[u:Z8_5’•U\EžBWL^oki6¿$¯ gZ½’–W¡XhU8\!gkU8p U ¬k˜-kZ8USW‚pokWLU’–Xh^B_ HX“’¡g}Š ’•Xhu Z1ik^BXh_’'v‚^Ç u Z8UfvyokW'Z8u Z8_’•c)¤ Z8USW‡USikUQWy’•cfXh_k~\œobp`Xh_Bž!’–gBU’U’6VkUvLZ\hX[_B@Z (¡‰ *¿ ¯)gBZ%iBWYXhu USW  Z_pfik^Xh_’ HUv—’–gBZ-t`gUSW¡ik$˜ #CUS_ pBZSW©™HZX 7pBZ­v7~^`W'Z (y¬k®fc ¬)¤ *•cU­vLZ8uÁX«˜ ŸobUS_5’¡X“’•U’–X«n`Z W'U8pBXh^\h^BžkXs~Eu€Z5Uv–okW'Z W'Z8~8^kuÁu Z8_BpBZpÁU5v‡^`_ZE^Çq’–gBZm3’ C^€iB^qvv'X‘Vk\[Z iBWYX[u USW €Z8_Bpfik^kXj_5’'v‡Xs_ Zn`U\‘obU’•Xh_fžvy’–W–ob~’dokW'US\‡pBU8u USžkZ (y¬B2¬ *¿¯)gBXsv!v'~^`W'Zc W'U_fžkXh_Bž ÇdW'^ku-®¼’š^½¥B¥q‹c±Uv7v'Zv7v7ZvZSWL^Jv'Xh^B_v<U_kp '^Xh_5’•˜Yv¡ikU8~ZÁ_BUQW¡W'^ !Xh_fž£v'ZSikUSWLU’•Z8\ ‚Xh_w’–gBZ€gBU8_Bpv$U8_Bp‚Ç¡Z8Z’7¿¯)gBX‘Wy4’ ˜š3’ C^ '^kXj_5’'v Xh_:’–gZHgU8_Bpqv$U_p1¤¬ Xh_!’–gBZEÇ¡Z8Z’)UQW'Z?v'~8^BW'Z8p!ǖ^BW‡ZSW•^Jv•Xh^`_qvLc HX“’–g€UEu:USÃkX[uHobu ^`Ç)¦CZSW'^qv'Xh^B_qv)ikZSW '^Xh_’Xj_’–gBZEgBU8_Bpv‡U8_p ¤Q® Xh_:’–gBZ€Ç¡Z8Z’7&¿ %7^`Xh_5’•˜Yv¡ikU8~ZH_USW¡W'^ €Xh_fž HUv žBW'U8pBZ8p‚ÇdW'^fuA® ’•^w¥ Xh_‚ŠB® L^`Xh_’'v$Xh_:’–gBZ!gBU8_pJv$U8_Bp‚Xj_¤¬ '^Xh_5’'vEXh_ ’–gBZwÇ¡ZZ’7¿6¯ gZ tBgBUQW¡ik$˜ #CU_¼pBZSW ™€Z8X 7pBZ vL~8^`WLZ:Xšv ’–gBZ v–oqu-^BÇ(’–gBZ ZSW'^qv'Xh^`_¼U8_Bp '^Xh_’•˜Yv•ikU8~8Z _BUQW¡W'^ !Xh_fžwv7~8^BW'Zv ¿ tkXju!ob\[U’–Xh^B_qv^BÇ \h^_fžkX“’dobpBXh_kU\wu Z8Ufv–okW'Z8u:Z8_5’'vXh_fnk^\‘nkZp o6v'Z ^Ç U©\hXh_kZUQWuÁX‘ÃbZ8pB˜•ZÇ–Ç•Z8~’'v u€^kpBZ8\ €X“’•g¼UHWLU_pB^u4Xh_5’•ZSW'~8ZSif’,US_p½v'\h^BikZf¿q¯)gBZ:Xh_kpBX«nkX[pobU8\)Xh_’•ZSWL~8ZSif’,US_Bp½v'\«^`ik+Z €ZSWLZ v'X[u!oq\[U’•Z8p ǖ^BW ZU8~8g@iqU’–X[Z8_’•c US_Bp@W'U8pBXh^BžBW'USiBgBX[~©pBU’•U HZSW'Z©v'X[uHob\[U’•Z8p €X“’–g U \[Xj_kZUSW u€^kpBZ8\wÇyWL^u’–gBZv7Z Xh_kp`X‘nbX[pobU\iqUQW'U8u:Z’•ZSWv¿qr\h\(v'Xsu!ob\sU’¡Xh^B_wnkU8\‘obZv HZSW'Zw~Sg^JvLZ_¼U8~8~^`W'pfXh_Œž ’•^ ifoBVB\hXdv'gkZ8p pBU’•U ^`DZ’–gZ ¯+†±|£5e .²vy’dobp  (y¬kŠB˜y¬q:¦ *7¿ &}ZwUvvyobu Z8p ’–gBU’ ’–gBZÁV`Ufv7Z\hXh_kZwpBXšv–’–W'X«VŒoB’¡X«^`_ ^BÇm’–gZ:W'U8pBXh^BžBW'USiBgBX[~ vL~8^BW'Z ~8^fok\hp V`ZwUSiBiBW'^fÃkXhu:U’•Z8p 2V £U¢\«^`žk˜y_^`W•u€U8\(pBXdvy’–W'X‘VfoB’–X[^`_ (yu€Z8U8_ '6¥q¦Œc,v–’•US_BpBUQW'p pBZnkX[U’¡X«^`(_ 'N¥q:¦ * ¿+¯)gBZ u Z8U8_@iBW'^BžBW'Zvv'X«^`_ ~8U8_©V`Z U5vvyobu:Zp ’•^;V`Z}\[Xh_kZ8USW (y¬k¾ *'c€U8\“’–gB^fokžBg ’–gZ—Zn`^\“oB’–Xh^B_ ^BÇ pBU’•UªÇ–^BW Xh_kp`X‘nbX[pobU\¼ikU’¡X«Z_5’'v—v'gB^ :v/gBXhžg%nkUSW'X[USVkXs\hX“4’  (y¬k‰ *¿w¯)gBZ v'\h^BikZ HUfv v'X[u!oq\[U’•Z8p 2V  U¨_B^BW'u€U\ pBXsvy’–W'X‘VfoB’•Xh^B_q¿.

(11) HAL author manuscript. kt Xju!ob\[U’–Xh^B_qv HZSW'Z@pB^B_BZªoq_pBZSW½’–gZ@U\œ’•ZSW¡_BU’¡X‘nkZ@U8_p ’–gBZ@_ob\h\ g2Bik^’–gZv'Xdv¿?ˆ€_pBZSW½’–gkZ U8\“’•ZSW¡_U’•X«n`Z!gBik^f’–gBZv'Xdv'c’–gZ v'\«^`ikZ€U8_Bp Xœ’'vEvy’•US_pBUSW'p‚pBZnkX[U’¡X«^`_HZSW'Z!Ufv7vyobu:Zp ’•^:VkZ?žBWLZ8U’•ZSW Xh_Á’–gkZ ~8^B_’–W•^`\‚žBW'^foki ’–gBUS_AXj_%’–gBZ ZSÃBikZSW'Xsu Z8_’•U8\‚žBW'^foki (–u:ZU_A~8gBU8_ŒžkZ¨^fnkZSW/¬ kZUSWv 'ŠBc½vy’•UQ_BpBUSW'p pBZnkX[U’•Xh^B_ ' ¤Q®Bcn6v ¿+u€Z8U8_ '®Bc(vy’•US_pBUSW'p pBZnkX[U’•Xh^`_£¦Œc W•Zv¡ikZ~’¡X‘n`Z1\ 2*'c CgBXs~8g WLZÇ–\[Z8~’'vǖZ" ZQW VkZ8_BZ8Ç¡X“’7v ÇdW'^u©’–WLZ8U’–u€Z8_’ (yX ¿“ZŒ¿“cBžBW'Z8U’•ZSW‡pBZ ’•ZQW¡Xh^BW'U ’–X«^`_€^kÇ v–’–Wyob~’[okW'U8\kpBUu USžk$Z *±Xh_!’–gBZE~8^B_’–W•^B\BžBW'^oki6¿5r@v'U8u€i\[Z v'1X 5ZEZv–’¡Xhu U’•Xh^`_€Ç–^BW‡Um3’ €^k˜Yv•XhpBZ8p?’•Zvy’^BÇZÇ–Ç¡X[~8U5%~  (š’•˜s’–Zv–4’ *)W'Zv–ok\“’•Z8pÁXh_ U?v7U8u€i\[Z?v'1X 5Z^`Ç ¤8¦Œ®!iqU’–XsZ8_5’'v ikZSW‡žBW'^fokiH’š^wU8~SgBX[ZSnkZU<3’ ŒiqZEƒ.ZSW¡W'^BW‡^`LJ:¦ 9U8_pwU<ik^ €ZQW(^BÇ)ÂB® 9¿5ˆ€_BpBZSW)’–gBZ_ob\s\6g Bik^f’–gBZv'XdvLc`’–gBZ u Z8U8_€~8gBU8_fžkZE^fnkZQW)'¬ Z8USWv‡Xh_€Z8U5~8g!žBW'^foki HUv6’–gBZ?v'U8u @Z (¡U8\dv'+^ !X“’–g¼¤8¦Œ®HikU’–XhZ8_’'v)ikZSW)žBW•^fok2i *¿. inserm-00217436, version 1 .  " . . .   .  . rÇs’•ZSW ’–gBZ ~8^`uCi\[Z’•ZªpBU’•U v'Z’'v €ZQW'Z v¡Xhu!ob\sU’•Z8pBc!ikU’–XhZ8_’'v :pBU’•U €ZSWLZªpBZ8\hZ’•Z8p@U8~~8^`WLpfXj_Œž©’•^¨U iBW'Z8pBZ8ǖXh_kZ8p uÁXdvv'Xh_Bžk_BZfvvu Z5~8gBU8_BXdv'uw¿+& Z©~8^B_v'X[pkZSW'Z8p ^`_B\%u Xšv7v'Xh_Bž%pU’•U €X“’–g U©u€^B_B^f’–^B_BZ ikU’[’•ZSW¡=_ (yXd¿œZf¿œc)pBU’•UÁǖ^BWEU€ikU ’–X«Z_5’(okiw’–^ U:~8ZQWš’•USXh_w’–XhuwZ%*¿ &}Z:U5vvyobu Z8p¢’–gU’$U8\h\ V`Uv7Z8\jXh_kZ pBU’•U HZSW'Z ^fVqv'ZQWynkZ8pq¿BŽqokWy’–gZSW±’–^ ^okW.iBW'ZnkXh^fo6v \hX“’•ZSW'U’dokWLZ?W'ZnkXhZ  (S¤Q¾ *'8c HZ!Uv7vyobu Z8pwU!pfW'^BiB^fof’–W'U’•Z^`ÇE¤8¦:9 U’ ¬ BZ5USW7v¿+eU’–XhZ8_’'<v €X“’•gpBXšv7ZUv7Z iBW'^BžBW'Zv7v'Xh^`_£žBW'Z8U’•ZQW€^`WC\h^ HZSW?’–gUS_U pBZ8ǖXj_kZ5p\sXhu:Xœ’?VbZ3’ HZ8ZS_¬ ^k~8~8Uv'Xh^B_v¼pfW'^BiBikZ8p—^fof’ ^BÇ!’–gBZ ’–W¡X[U\ ¿ ¯±gZ1iBWL^V`UVkXs\[X“-’  ^Ç pfW'^`ik^fof’ HUv (¡X *w¬6¿‘:¦ 9 Xjǀ’–gkZ>v'\h^BiqZ VkZ3’ €Z8Z8_!¬wv–ob~8~8Zfvv'X‘nbZ nkXšv'Xœ’v HUv‡_BZQžkU’¡X‘n`@Z (LX ¿“ZŒ¿“ckXju€ikW'^fnkZ8u€Z8_4’ *'2c (–Xj1X *(:¦ 9-XhÇJ’–gkZ?v'\«^`ikZ HUv)VkZ3’ HZ8Z8_ ® US_p½¦wik^Xh_5’'@v (yX ¿“ZŒ¿“c±v'\hXhžkg’$pBZ’•ZQW¡Xh^BW'U ’–X«^`_ *EU8_B!p (¡XhXs1X *$¬k® 9 XhÇ(’–gBZ¢v'\«^`ik+Z €Ufv$žBW'Z8U’•ZSW(’–gZS_½¦ ik^Xh_’'v (¡Xd¿œZf¿œc±vyoBVbvy’•US_5’¡XhU8\‡pkZ’•ZSW¡X«^`W'U’–Xh^`_ *@(YvL~8Z8_BUSW'Xh^ @r *¿6¯)gBZw\sXsu X“’$^BÇE¦wik^Xh_’'v €U5vE~8gB^qv'Z8_ Xh_£U8~8~^`W'pBUQ_B~8Z €X“’–gifokVk\hXdv'gkZ8p>Zfv–’–Xju U’•Xh^B_qv ^`ÇE’–gBZ u:Xh_kXju U5\E~8\hXj_kX[~5U\h1\ ªX[uÁik^BWd’•US_’HpfXhÇyǕZSW'Z8_B~5Z U8_Bp ’–gBZ v'u U8\s\[Zvy’ pBZ’•Z8~’•UVk\[Zp`XhǡǕZSW'Z8_B~Z!^`Ç6’–gBZ:tBgkUSW•ik$˜ #!UQ_:pkZSW)™€Z8X 7pZ€v'~8^BW'Z88c CgBXh~8gwUQW'Z<nkZQW  ~8\h^qv'+Z (•USiBiBW'^fÃkXju U’•Z81\  ¦£ik^`Xh_’'>v * (y¬)¤ *¿)ƒ¡_ªvL~8Z8_BUSW'Xh^/rc,’–gBZ iBW'^fVkUVkXs\sXœ-’ 1^ǀU u€Xšvv'Xh_Bž>n`U8\«obZ HUv USW¡VkX“’–W'UQWYXh1\  ~g^JvLZS_ ’•^ ZS_qv–okW'Z?UpfW'^BiB^fof’W'U’•ZE^`ǍUSiBiBW'^fÃkXhu:U’•Z1\  ¤8:¦ 9 U’+’–gZ<ǖXh_kU\qnkXdv'X“’7¿fƒ•_ v'~Z_USW'Xh^Á]c`’–gBZEiBW'^fVkUVkX[\sX“4’  ^Ç UEuÁXdv7v'Xj_Bž€nkU8\‘obZ €U5v‡p`X‘nbX[pBZ8p?2V €¬!’–^:U~SgBXhZSnkZEUEpfW'^BiB^fof’JW'U ’•Z$^`ÇUSiBiBWL^ÃkXhu U’•Z8\ €‰q¿‘:¦ 9¿.

(12) . "      !  ".  . . . HAL author manuscript. ¯)gBZ ¬k˜Yv'X[pBZ8p½’•˜s’•Zv–’@€Uvo6v'Z8p½’š^½’•Zvd’ ’–gZ UV6v'^k\“oB’•Z ~SgU_ŒžqZ V`Z’3€ZZS_½’–gZ ¬žBW'^fokiqv (yiBW•^`žBWLZvv'Xh^B_ Zv–’–Xju U’•ZpC2V C’–gBZE~SgkU8_fžkZmV`Z3’ HZ8Z8_?’–gBZmV`Uv7Z8\jXh_kZEU8_Bp€¬k˜-BZUSW+nkXdv'X“’4*¿ r \hXh_kZ5USW¨uH^pBZ8?\ €X“’–g u X«ÃbZp Z8ǖǡZ~’'v ǖ^`W W'ZSikZ8U’•Zp uHZ8UvyokWLZu Z8_’'v €X“’–gW'UQ_BpB^u Xh_’•ZSWL~8ZSif’'v/U8_Bp²v'\h^BikZ?v  Uv U8\dv'^A~8^`_kv'X[pBZSW'Z8pq¿ ¯ gBX–v/u€^pBZ8\w’•%U #kZv/Xh_’•^AU8~8~8^fok_’ÆXj_5’•ZSW¡u Z8pBX[U’•Z u Z8UfvyokW'Z8u Z8_’' v (y_B^f’ yovy’¬/u:ZUvyokW'Z8u Z8_’'>v *¿ &—X“’•g>u Xšvv'Xh_Bž/pBU’•Uc.’–gBXdv€u€^kpBZ8\(o+vLZvHU8\s\EUSn`UX[\[UVk\[Z u Z8UfvyokW'Z8u Z8_’'v ¿JlZv–’–W¡Xh~’•Z8p u€USÃkX[uHobu-\s1X #kZ8\sXhgB^k^p Zv–’–Xhu:U’¡Xh^B_ HUvEikZSW'ǖ^BW¡u Z8pq¿6ƒ¡_ ’–gBZ:uH^pBZ8\hc+’–gBZ Xh_’•ZSWLU8~’•Xh^`_ ^BÇ+žBW'^fokiÁ2V €’•Xhu:Z^BÇ+nkXšv7X“’ (LX ¿“ZŒ¿“cB’–gBZp`XhǖǡZ8W'ZS_~8Z?Xh_ v'\h^BikZv *5HUv U?ǖX‘ÃbZ8p:Z8ǡǕZ8~’7¿Œr Ž˜š’•Z5vy’ ^B_<’–gBXdv‡ÇyX‘ÃbZ8p€Z8ǖǡZ8~’ HUv+o6vLZ8p?’–^€~8^Bu!ikUSW'Z?v'\«^`ikZv ¿. inserm-00217436, version 1 . "      ! . . &}Z:~8^B_v'X[pBZSW'Zp Š. .  . u Z’–gB^kpv$^BÇ(u U_USžkXj_Bž u€Xdvv'Xh_Bž pkU’•Uf¿b¯ gZC’3C^‚ÇyX‘Wv–’ u€Z’–g^pv$USWLZC’–WLU8p`Xœ’–Xh^`_kU8\h\  o6v'Zp'(Q¤Q¾*'cUQ_Bp?’–gBZm’–gBX‘WLpÁ^B_BZEXdv)iBW'^u€Xdv'Xh_Bž6¿.ÇJ’–gZ<ǕXsWv–’q’3C^Áu€Z’–gB^kpv'cf’–gBZE~8UvLZ8˜¡~8^ku!i\[Z’•ZEUQ_BU8\bv'Xyv Xhž_^`WLZv ’–gBZ:iBWL^Vk\[Z8u^BÇEu:Xdvv'Xh_fžÆpBU’•Uf7¿ &—gBZ8_£~8^B_v'X pBZSW'Xj_Œž£UV6vL^\“oB’•Zw~SgU8_fžbZ8c’–gZw~8Ufv'Z8˜•~8^u!ik\[Z’•Z US_U\1qv7Xdv UÇ•Ç¡Z8~’'v ^`_B1\ /ikU’¡X«Z_5’'+v €X“’–g ~8^Bu!i\[Z’•Z pBU’•U (¡Xd¿œZf¿œc ~^`u!ik\[Z’•Z pBU’•U U’VkUvLZ\hXh_kZ U8_p>Ç¡Xh_kU\ nkXdv'X“’7v *¿fƒ•_:U\sXh_kZ8USW(u X‘ÃbZ8pB˜¡Z8ÇyǕZ8~’'v.u€^kpBZ\«c`’–gBZ!U8_U1\ qv'Xdv‡W'Z8Ç¡ZQWv)’•^wUS\h\+USn`UX[\[UVk\[Z?u Z8Ufv–okW'Z8u:Z8_5’'v¿B¯)gBZ v'Z~8^`_p€U_pÁu€^qvy’i^`ifok\hUQW±u€Z’–gB^kp!^`Ç)v'Xh_Bžk\sZEXhu€ifoB’•U’dXh^k_ €U5v+’–gBZE\hUfvy’^fVqvLZSWynbU’–X«^`_€~USW¡W'X[Z8pÁǖ^B-W HUSW'p (š/§ . ±,Ž *:u Z’–g^pBc !gZSW'ZS2V ’–gBZ \sU5vy’H^Vbv'ZSWyn`U’•Xh^`_/Xdvw~USW¡W'XhZ8p>ǖ^B-W HUSW'p/US_Bp o6v7Z8p>ǖ^BW U8\j\Eu€Xdvv'Xh_ž ^fVqv'ZQWynkU’•Xh^B_qv‡U’6’–gBZ WLZu U8Xh_BXh_BžÁ’–Xhu Z<ik^Xh_5’'v¿Œ¯ gZm’–gBX‘W7pÁu€Z’–g^p HUv‡u!oq\“’•Xhi\[ZEXsu€ifoB’•U’–Xh^B_ (y¬q‹ŒcB¬k *¿ ƒ¡_kvy’•Z8U8p€^BÇ+ǖXs\[\jXh_Bž Xj_ U?v'Xh_Bžk\sZmnbU8\“oJZEǖ^`W‡Z8U~Sg€uÁXdvv'Xh_BžÁn`U8\«obZc’–gBXsv’•Z8~SgB_BX[ŸobZ W'ZSik\[U8~8Zv‡ZU~8g€u€Xdvv'Xj_Bž nkU8\‘obZ^Ç)US_ Xh_k~8^u!ik\[Z’•Z?pBU’•UHvLZ ;’ !X“’–g U!v'Z’^BÇ+ik\[Uo6v'XjVk\[Z<n`U\‘obZ/v (¡_ ')¦€Xh_ ^okW vy’dobp  *)’–gBU’W'ZQiBW'Zv'ZQ_’ ’–gBZÁok_~8ZSWy’•U8Xh_4’  Xh_ ’–gBZw~8^BW¡W'Z~’ nkU8\“obZÁ’•^½Xhu!ifoB’•ZŒ¿+¯)gBZwpBU’•UwUokžBu:Z8_5’•U’–Xh^B_ |/^B_’•Zw  USW'\h^ |/USW #k^fn.

(13) HAL author manuscript. ~SgUXh_@W'ZQi\[U5~8Z8u Z_5’ uHZ’–gB^kp0€U5v o6v'Z8pq¿¯±gZ_c€Z8U8~8g ~8^Bu!i\[Z’•Zp@pBU’•U v'Z’ Xdv U8_U\12ŒZ8p©V2©’–gkZ US_U1\ qv7Xdv ^LJ~8gB^kXs~Z8c6U_p:W'Zv–oq\“’7v ^BÇ(X[uÁifoB’•ZpwpBU’•Uv'Z’'v(UQW'Z!~8^u!VkXh_kZ8pwXh_‚U v'Xh_Bžk\[ZÁU8_U\1qv'Xdv kXsZ8\[pBXj_Bž ik^BXj_5’Zvy’–Xhu U’•Zv‡UQ_Bp:vy’•US_pBUSW'p€ZSW¡WL^fWv¿ |/Z’–g^pv ^`ǂu U8_BUSžkXh_Bž¨u Xšv7v'Xh_Bž pU’•U US_Bp@pBU’•U US_BU8\ bv'Xdvvy’–W'U’•ZQžBXhZfv HZSW'Zª~8^kuHVkXh_kZ8p (¡¯‡UVk\hZ:¤ *‡US_p€USiBi\[X[Z8p?’–^?’–gBZ ¬wv'~ZS_BUSW'Xh^qv'cBr U8_Bp?]cB^`ÇuÁXdvv'Xh_Bž pBU’•Uf¿.            " . inserm-00217436, version 1. ¯)gBZ ’-ŒikZEƒ(ZSW•W'^`W.US_pÁik^€ZSW‡^BÇN’–gZ’•˜d’•Zvd’‡US_pHŽ‚’•Zvy’ok_BpBZSW.p`XhǡǕZSW'Z8_5’‡USiBiBW'^kU8~SgZv5€ZQW'Z?~^u!ifoB’•Z8pq¿ ¯‡^@Zvy’–Xhu U’•Z ’–gBZªZ8u!ikXhWYX[~8U8\?’4ŒiqZ/ƒ ZSW¡W•^`W‚^BǂZ8U8~8g USiBiBW•^kU8~SgBc?’–gZªZS_’•X‘W'Z’–W¡XhU8\wv'Xju!ob\[U’¡X«^`_ €Ufv W'ZSikZU’•Z8p>¤Q®B®B®¢’–Xhu Zfvmob_BpBZQWm’–gBZw_ob\s\‡g Bik^f’–gBZ5v'Xšv ¿6¯±gBZwZ8u€ikX‘W'Xs~5U8\+4’ fikZ€ƒZSW¡W'^BW HUv~8U8\[~oq\[U’•Zp Uv ’–gBZwiBW•^`i^`Wd’–Xh^B_ ^BÇme nkU8\‘obZ

(14) v —®q¿œ®¦¼ÇdW'^`u²’•Zv–’–Xj_Œž½’–gZ¢_5oq\[\(g Bik^f’–gBZv'XdvC^BÇE_B^pfXhÇyǕZSW'Z8_k~8Z‚Xj_£Z8U~g v'Xhu!oq\[U’•Z8p ’–W¡X«U\–¿‡tX[u:Xs\[USW'\ kc+’•^ Z5vy’–Xhu U’•ZÁ’–gBZwZ8u€iXhW'X[~5U\)ik^ HZSW^`ÇZ8U8~8g£USiBiBW'^kU8~Sgc’–gZ Z8_’–XzW'Z ’–W•XhU8\ v'Xhu!oq\[U’•Xh^B_  Uv)WLZSikZ8U’•Z8p ¤Q®B®B®?’•Xju Zvoq_pZSW+’–gZEU8\“’•ZSW'_BU’•X‘nkZEg Bik^f’–gBZv'Xdv ¿f¯)gkZEZfvy’–Xhu U’•Z8p!ik^ HZSW)ǖ^BW Z8U8~8g USiBiBW'^kU8~Sg HUv/’–gBZ¨iBW'^Bik^BWš’–Xh^B_²^BÇ ’–gBZ5v7Z¤8®B®B®v'Xhu!ob\sU’•Z8p ’–W¡XhU8\dv@v'gB^ €Xh_fžv–’•U’–Xsvy’•Xh~8U8\[\  v'X‘žk_BXsÇ¡X[~8U8_5’+WLZvyob\“’'v (š e ¼®q¿œ®¦ *¿ ˆC_BpBZSW‡’–gBZ!U8\“’•ZSW'_U’¡X‘n`ZHg ik^’–gZv'Xdv (¡Xd¿œZf¿œc’–gBZ?g ik^’–gZv'Xdv ^BÇ(UE’–W'Z8U’–u€Z8_5’.ZSÇyǕZ8~4’ *LcNZ5vy’–Xhu U’•^fWv ^BÇ ’–W'ZU ’–u€Z8_5’ Z8ǖǖZ~’ HZSW'Z€~Q^`u!ifoB’•Zp )¯+W'Z8U’–u€Z8_’,ZSÇyÇLZ8~’ €Uv‡’–gBZ€pBXjǖǕZSW'Z8_B~5ZÁXh_:’–gZÁUSVbv'^\“oB’•Z€u€Z8U8_ ~SgU_ŒžqZ!VkZ3’ HZ8ZS_:’–gZ!¬ žBW'^fokiqv(2V w’•˜š’•Zvd’,US_BU8\ qv7Xdv$^`W$Zv–’–Xhu:U’¡Xh^B_‚^Ç.p`XhǡǕZSW'Z8_~8ZÁXh_ v'\h^BikZv VkZ3’ HZ8Z8_ ’–gBZ¬wžBW¡^fokiqv±2V  \jXh_kZ5USW u€X‘ÃbZ8pB˜¡Z8ÇyǕZ8~’'v,US_BU81\ qv7Xšv ¿Br<n`ZWLUSžXh_Œž:’–gBZ!Zv–’–Xhu:U’•Zv pBZSW'X‘nkZp¢ÇdW'^ku¨’–gBZ ¤Q®B®B® v'Xhu!oq\[U’•Z8p ’–W•XhU8\šv£U8\[\h^ HZ8p@ǖ^`W Zv–’–Xhu:U’¡Xh_fž©’–gkZ ZÃiqZ~’•Z8p@u€Z8U8_@^Ç:’–gZ1’–W'Z8U’–u€Z8_’¼Z8ÇyǕZ8~’7¿¯)gBZ8_ ~8^Bu!ikUSW'Xh_Bž¨’–gBXdv/ZSÃBikZ8~’•Z8p u:ZU_@’•^ ’–g Z ’–WyobZ  nbU8\“obZ (šo6vLZ8p ’•^4v'Xhu?oq\[U’•Z pBU’•%U *ÆU\h\h^ HZ8p ǖ^BW ~8U8\h~ob\[U’•Xj_Œž ’–gBZ!VkX[Uv ¿`]XsUfv  U5vEZSÃBiBWLZvv7Z8p‚Ufv W'Z8\[U’¡X‘nbZ!VkXsU5@v (¡Xh_ ikZQW'~8Z8_’•USžk$Z * U8_p Ufv$USV6v'^\œoB’•ZCVkX[Ufv (¡Xh_wtBgBUSW¡ik˜dnkU8_€pBZSW+™HZ8Xhp 7Zmob_BX“’'v * ¿.

(15) HAL author manuscript. ¯ ŒikZ€ƒEZSW¡WL^fW'c+iB^€ZQW UQ_Bp VkX[Uv HZSW'Z U8\švL^ ~8^u!ifoB’•Z8pwVkZ8ǖ^`WLZH’–gBZ:u€Xdvv'Xh_Bž_ZfvvEu Z8~8gBU8_BXdvu HUv‡USiBik\sX[Z8p (¡Xd¿œZf¿œc^B_€~8^Bu!ik\[Z’•ZEpBU’•U?v'Z’'v)ǖ^BW!gBX[~8g US_ 8X[pBZ5U\ U8_BU8\1qv'Xdv.~8^ok\«pHVbZ ikZSW'ǖ^BW¡u Z8p*‡Uv‡U W'ZSǕZSW'Z8_~8ZEU8_Bp?’–^€~SgZ8%~ #!’–gBZmn`U\[X[p`X“4’ H^Ç)v'Xsu!oq\[U’•Xh^B_v ¿ tkXju!ob\[U’–Xh^B_qv^Ç(’–W¡XhU8\dv!Xh_fnk^k\«nbZp¼o6v7Zw^BÇml ¬6¿ ¬6¿œ®q¿J|1US_BUSžkZ8u Z8_’^BÇ u:Xdvv'Xh_Bž£pBU’•UwU8_Bp pBU’•U US_U1\ qv7Xdv±Xh_fn`^\‘nbZ8pwt`r€t Âq¿d¤5¿. inserm-00217436, version 1 .

(16)      . HAL author manuscript inserm-00217436, version 1. ˆC_BpBZSW(’–gBZ€U8\“’•ZSW•_BU’•X‘nkZÁgik^’–gBZv'XdvLcJ’–gBZ€u€Xšvv'Xh_Bžk_BZvv u Z8~8gU_BXdv7u%iBW'^nkX[pBZ8p‚UÁu€Xdvv'Xh_Bž pBU’•UHWLU ’•Z!U’ ¬ Z8USWv.^`Ç$¤8¦k¿œŠ 9ǖ^`W v'~Z_USW'Xh^wr@U8_Bp ‰q¿“ 9 ǖ^`W v'~8ZQ_BUSW'Xh^Á] (•¯±USVk\[Z<2¬ * ¿eW¡^BiB^BWš’–X«^`_kv(^kÇ)pfW'^Bik^oŒ’)Xh_  v'~Z_USW'Xh^:r©Ç–^BW‡~8^B_BpBX“’•Xh^_v‡X[cX[XqU8_Bp:XhX[X €ZQW'Z ¬6¿‘:¦ 9 cJ¦k¿ ® 9-US_Bp!¬k®q¿œ® 9 cBW'Zv¡ikZ~’¡X‘n`Z1\ b¿fƒ¡_wv'~8Z8_kUSW'Xh^!]c ’–gBZ5v'Z iBW'^BiB^fWd’–Xh^B_qv‡U8\švL^:USiBiBW•^fÃkXju U’•ZpÁZÃBikZ8~’•ZpCn`U8\«oJZv (Q¤5¿Ä2¬ 9¼cB¬q¿‘:¦ 9-US_Bp ¤Q®q¿d¤ 9 cfW'Zv¡ikZ~’–X‘nkZ8\ *¿ Ž^BW©vL~8ZS_kUSW'Xh^²r ob_BpBZQW>’–gBZ _ob\s\£g Bik^f’–gBZv'XdvLc¼3’ ikZ¨ƒ—ZSW•W'^fWv HZSW'Z u€U8Xh_’•U8Xh_kZ8p (¡Xd¿œZf¿œc USiBiBW'^fÃkXhu U’•Z8\  :¦ 9!*;ZÃ`~8ZSif’ ǖ^BW ’–gBZ4ǖ^k\j\«^ €Xh_Bž vy’–W'U’•ZSžBXhZfvQ ’–gBZ²~Uv7Z8˜¡~8^Bu!ik\[Z’•Z4U8_Bp/§ . ,Ž USiBiBW'^kU8~SgZv?2V ¼’•˜š’•Zvd<’ (yX ¿“ZŒ¿“5c !gZS_£~8^u!ikUSW'Xh_BžUSVbv'^\‘oB’•Z‚~SgBUS_Œžk%Z *'c(UQ_Bp ’–gZ § . ,Ž}USiBiBW'^kU8~Sg 2V  Ž ’•Zvd’ (yX ¿“ZŒ¿“c CgBZ8_¼~8^Bu!iqUQWYXh_Œž v'\h^BikZv$2V  \[Xj_kZ5USWEu€X‘ÃbZ8p Z8ÇyǖZ5~’,u€^pBZ8\ * (¡¯‡UVk\[Z:Š *¿h¿qr!vZÃikZ8~’•Z8pBcN’–gZ ik^ €ZSW.ǖ^`W ~^`u!ik\[Z’•Z!pBU’•U€v'Z’'v (yXd¿œZf¿œc €X“’–gB^foB’‡u€Xdvv'Xj_kž‚pBU’•%U * €Uv,~8\h^JvLZ<’•^‚ÂB® 9 !gU’•Zn`ZSW±’–gBZCpBU’•U US_U1\ qv7Xdv<o6vLZ8?p (•UVbv'^\œoB’•Z ~SgU8_fžkZ‚^`W\hXj_kZUSW!u€X‘ÃbZ8pB˜¡Z8ÇyǕZ5~’'vu€^kpBZ\ *¿N] /vL~8Z8_BUSW'Xh^^BÇEu€Xšvv'Xh_BžÆpBU’•U US_0 p €gBZ8_@pBU’•U €ZQW'ZªUS_U\ fZp@UÇs’•ZQW o6v'Xh_fž Xju€ifok’•U ’–X«^`_—’•Z8~SgB_BX[ŸobZv (¡Xd¿œZf¿œc?/§ . .Ž ^`W uoq\“’•Xhi\[Z Xsu€ifoB’•U’–X«^`_ *^`WE_^@’ (–Xd¿œZf¿œc±~8U5v'Zw~8^uCi\[Z’•%Z *Lc i^ HZSWEW'U_fžkZ8p ÇyWL^`u ¦6¤ 9 (š’–˜s’•Zv–’ ikZQW¡Ç–^`W•u€Z8p ^`_ ~U5v'Z8˜ ~8^Bu!ik\sZ’•ZEpBU’•U €X“’–g^oB’u€Xdvv'Xj_Bžk˜•pBU’•U gBU8_BpB\sXh_Bž u:Z’–gk^p>v *N’–^ ‰f2¥ 9 ( ’•˜s’•Zvd’^B_€u:Xdvv'Xh_BžwpBU’•U gBU8_BpB\[Zp V2 u!oq\“’•X‘ik\[Z<X[uÁifoB’•U’–Xh^`_ *¿ &—gBU’•ZnbZSW+’–gBZEpBU’•UEUQ_BU8\ qv7Xyv'cf’–gBZEU8\h\h˜'USnkU8Xs\[USVk\[ZEpBU’•UEUS_pC/§ .C ,Ž¼u:Z’–gB^kpv žkUn`Z:Z8ŸobX‘nbU\[Z8_’,ik^ HZSW7¿] ¼u!oq\œ’¡X‘ik\[Z:Xsu€ifoB’•U’–Xh^B_Bcq’dgZÁik^ €ZSW €U5vEU8\ H%U qvEgBXhžkgBZSW ’–gBUS_w’–gBU/’ !X“’•g ^’–gBZQW)Xju€ifoB’•U’–X«^`_:v–’–W'U’•ZSžBX[Zv (¡¯‡UVk\[ZEŠ *¿ r€v.ZÃikZ8~’•Z8pBcB’–gBZ VkXsU5v(^kÇN’–W'Z8U’–u€Z8_’‡ZQÇyǕZ5~’ CX“’–g ~8^u€ik\hZ’•ZpBU’•UHvLZ’'/v (yXd¿œZf¿œ8c €Xœ’–gB^fof’)u€Xdvv'Xh_ž pBU’•%U * €U5vmn`ZSW  \h^  (¡Xd¿zZf¿œc)~8\h^JvLZH’•^ ® 9=* CgBU’•Zn`ZSWm’–gZ:pkU’•U:UQ_BU8\ bv'Xšv (¡¯±USVk\[Z:Š * ¿Ž^`Wv'~8Z8_USW'Xh^½rc €X“’–g ¤8¦k¿œŠ 9 u€Xdvv'Xh_Bž—pBU’•U U’C¬ Z8USWvLcm’–gBZ ’–WLZ8U ’–uHZ_5’ ZSǖǡZ~’ Zv–’–Xju U’•Zp12V ª\[Xh_kZ8USWwu€X‘ÃbZ8pB˜¡Z8ǡǕZ8~’ u€^kpBZ8\ €X“’–gªu!ob\“’¡Xzi\[Z Xsu€ifoB’•U’–X«^`_/USiBiBWL^U8~Qg HUv€oq_pBZSW'Zv–’¡Xhu U’•Z8p12V  ¤Q‰q¿œ‰ 9 (¡Z8ŸobX‘nbU8\sZ8_5’?’š^ªUS_ ok_BpBZQW'Zvy’•Xhu U’¡X«^`_ ^Ç(®q¿‘¦ŒŠ:ik^BXh_’'v Xh_ tgUSW¡ik˜ynkU8_wpBZQW,™HZ8Xhp Z?ob_BX“’'v * (¡¯±UVk\sZ€Š *¿k¯)gBXdvmVkX[Uv HUv$\h^ HZSW ’–gBUQ_’–gU’/^fVf’•UQXj_kZp €X“’•gAU8\s\h˜'USnkU8Xs\[USVk\[Z8˜¡pBU’•U (¡˜y¬q¦k¿ ® 9!*/^`W/§ . .Ž (¡˜¡Š¦k¿ 2¥ 9!*/u Z’–gB^kpv¿ &—gBZ8_ ~8^B_v'X[pBZSW'Xh_fž;UVbv'^\œoB’•Z~SgkU8_fžkZ8cUSžkU8Xh_Bc!u?ob\“’¡Xhik\[Z1X[u:ifoB’•U’–Xh^`_ žkUn`Zƒ–gZ1uH^Jv–’:iBWLZ8~8XšvLZ½’–W'Z8U’–uHZ_5’•˜ Q.

(17) HAL author manuscript inserm-00217436, version 1. Z8ÇyǕZ8~’HZv–’–Xju U’•Z5v (šok_BpBZSWLZvy’•Xhu:U’¡Xh^B_/^BÇ ¤Q‰q¿ ¬29nqv ¿bŠf¥6¿œ®9 US_BpbŠ¦k¿‘‹:9ǖ^`W ~8U5v'Z8˜¡~^`u!ik\[Z’•Z US_Bp §/. ,ŽcBW'Zv•ikZ8~’–X‘nkZ8\ *¿ Ž^BW(v'~ZS_kUSW'Xh^H]cf3’ ŒikZ<ƒ‡ZSW•W'^`W HUv‡u€U8Xh_’•U8Xh_kZ8pÁǖ^BW‡U8\h\ v–’–W'U’•ZSžBXhZfv+ob_BpBZSW+’–gZ<_5oq\[\qgBik^f’–gBZv'Xdv ¿ lZvyob\“’'v oq_pBZSWm’–gZ:U8\“’•ZSW'_U’–X‘nbZ:g Bik^’–gBZ5v'Xšv €X“’•g¼‰q¿“ 9 u€Xšvv'Xh_Bž pBU’•U:U’ ¬ BZUSWv!v'g^HZ8p \hZvv VkX[Ufv ’–gBUQ0 _ €X“’•g v'~Z_USW'Xh^¨r VŒoB’‚Ç–^\h\h^ €Z8p USiBiBW'^fÃkXhu U’•ZS\  ’–gBZ©v'U8u Z>ibU’s’•ZQW¡_ (¡¯‡UVk\[ZªŠ *¿ ]XsU5!v €Ufv u:Xh_kXsu U8\ €X“’•g u!ob\“’•Xjik\[Z Xsu€ifoB’•U’–X«^`_ (¡˜Y‹k¿œ¾ 9ǖ^BWCUVqv7^B\“oB’•Z‚~SgkU8_fžkZ‚U_p 6‹k¿ 2¬ 9ǖ^`WC\jXh_kZ8UQW!u:X‘ÃbZ8pB˜ Z8ÇyǕZ8~’'v u€^pBZ8\ * US_Bp/ik^ HZS'W HX“’–gªu?ob\“’•Xjik\[Z XhuÁifoB’•U’dXh^_ HUv:VkZ’d’•ZSW?’–gBUQ_ €Xœ’¡g ^’–gZSW:Xhu€ifoB’•U’–Xh^B_ vy’–WLU ’•ZSžBX«Zv ¿.

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(21) HAL author manuscript inserm-00217436, version 1. u!oq\œ’¡Xhik\sZ€XhuÁifoB’•U’–Xh^`_wžkUSn`Z¢vyokVqv–’•US_’•XhU8\s\1 X[u€iBW'^n`Z8p:nkU8\‘obZv$ǖ^BWmik^HZSW$US_Bpwu€Xj_kXsu X15Z8p:’–gBZHVkX[Ufv$Xs_ Zv–’–Xju U’•Z5vE^BDZ’–W'Z8U’–u€Z8_’$Z8ǖǡZ8~’$Uv~8^`uCikUSW'Z8p HX“’¡g¼^’dgZSWEUQiBiBW'^U~SgBZv ¿™€^HZnkZSWLcN’–gBXšv$W'Zv–oq\œ’$~8^fok\sp VkZ—Xsu€iBW'^fnkZ8p©2V  Xj_k~8\‘obpBXj_Bž Xj_@’–gBZ—XhuÁifoB’•U’–Xh^`_ uw^kpBZS\wv7Z8\[Z8~’•Z8p ~8^fnkUSW'XhU’•Z5vvyob~8g Uv VkUfv'Z8\sXh_kZ iBW'Z8pBXh~’•^fW7v)^BÇpfW'^`i^oŒ’^fW‡~Q^`W–W'ZS\hU’•Z8p?nkUSW'X[USVk\sZ5v‡^Çq’–gBZ W'Up`Xh^BžBW'USiBgBX[~?vL~8^`WL@Z (¡ŠB‰ *¿ r HZ8\s\[˜¡pBZfv'X‘žk_kZ8p v–’dobp —v'g^ob\hp—U8\ H%U qv ~8^B_qv'XspBZQWÁ’–gBZ iBW'^fVk\sZ8u ^ǀu€Xh_X[u:1X 5Xh_Bž u Xdvv'Xj_Bž pBU’• U (¡Zf¿ žq¿œc+ZQ_vyokW'Xh_Bž USiBiBWL^`iBW¡X«U’•Z:ǖ^\h\h^ €˜šoki ǖ^BWEU8\h\)W'US_pB^u€X Z8p ikU’•XhZ8_’'v 2V v'~8gZ8poq\[Xh_Bž ikU’•XhZ8_’'v ǖ^BW?W'Up`Xh^BžBW'USiBg ÆZSnkZ8_£XjÇ ’–g%Z pfWL^`i£^fof’^`Ç ’–gBZ vy’dobp 2*(¡ŠB *¿(t’•U’–Xsv–’¡Xh~U\ u Z’–g^pvLc±gB^ €ZnkZS@W €Z8\[\ pBZv'Xhžk_BZ8pBc)~8U8_B_^’$UpBpW'Zv7vEu€Xdvv'Xj_Bž nbU8\“oJZv^Ç gBXjžkg iBW'^BiB^fWd’–Xh^B_qv¿qƒ¡_¼^fokW H^fW #kcJ’–gZÁiBW'^BiB^fWd’–Xh^B_ ^Ç u:Xdvv'Xh_Bž nkU8\‘obZv HUv!v–oqǖǡX[~8XsZ8_5’¡\  \h^  (¡Xd¿œZf¿œc)‰q¿“ 9 ^fW€¤8¦k¿“Š 9=*?v•^ Uvm’š^ VkZÁWLZ8Uv'^B_BUSVk1\  ~8^B_qv'XhpkZSW'Z8p €X“’–g v–’•U’–Xsv–’¡Xh~U\)u Z’–g^pv ¿`™C^ €ZnkZSW'c)v'^Bu€Z:vy’•U’–X[vy’•Xh~8U8\)USiBiBWL^U8~QgBZv$pBZ8U8\[Xj_B ž €X“’–g‚u:Xdvv'Xh_fž¼pBU’•U€~8U8_ u:Xh_kXsu€1X ŒZ½VkXsUfv HX“’¡g W'Z8UvL^`_UVk1\ —\h^  W'U’•Zv‚^BÇ:u€XdvSv'Xh_fž pBU’•U½VŒoB’ ~8US_B_B^f’ Un`^`X«p X“’ ~8^uCi\[Z’•Z8\ c ikUSWy’–X«~oq\[USW'\ +€Xœ’¡g:vLZ8\sZ~’¡X‘n`ZEpfW'^`i^oŒ’7¿ ¯)gBXdv vy’dobp wgUfv ~8USnkZU’'v US_p¢\[Xsu X“’•U’•Xh^`_kv¿fŽXhWvy’•c`’–gZv'Z!W'Z5vyob\“’'v u€%U ‚_B^f’)VkZ?žkZQ_BZSW'U8\[X UVk\[Z<’•^ U8\h\NWLU8p`X«^`žBW'UQigBX[~:v'~8^BW'Zv‡o6v'Z8pwXh_¢lr€¿f†±n`Z_‚XhÇ v'Xsu Xs\[U8W(W'Zv–oq\œ’'v Xj_wWLZ\[U’•X‘nkZ?VkX[Ufv ~8^foq\«p V`ZÁZSÃikZ8~’•Z8pBc Z̒–W'USik^B\hU’•Xh^`_’•^ÁUQ_B^’–gBZQW)W'U8pBXh^`žBWLUSiBgBX[~?v'~8^BW'Z H^ok\hp€W'Z8ŸobX‘W'ZEU _k"Z  v'Xsu!ob\sU’¡Xh^B_:v–’dobp b¿ktZ~8^`_pBc’–gZ W'US_pB^u v'Xsu!ob\sU’¡Xh^B_v ~USW¡W'XhZ8p/^oB’Cu€%U  _B^f’W'ZSǖ\sZ~’€U8\h\m’–gZ ikU’s’•ZSW•_v ^BÇ!u:Xdvv'Xh_fž pBU’•U ’–gBU’H~Q^ok\hp ^k~8~okW(Xh_:WLZ8U8\ v'Xœ’dobU’¡X«^`_kv¿`ŽbokWy’–gBZSW'u€^BW'Z8c HZ!pfXhpw_B^f’.Z Ãi\«^`W'ZCU\[\+u Z’–g^pv,^`LJpBZ8U8\[Xj_Bž HX“’¡gwu€Xdvv'Xh_ž pBU’•Uf¿8eUSWd’–Xh~ob\sUQWY\ `cq  ^^ # US_p:U8\d¿fgUnbZ iBWL^`ik^qv'Z8p€U?v•iqZ8~8XhÇ¡X[~Eu:Z’–gB^kpC’•^ pBZ8US2\ €X“’–g pBU’•UEu€Xšvv'Xh_Bž _B^f’ U’ WLUS_BpB^Bu€c €gBX[~g‚o6v'Zfvu€Z5UvyokW'Z8u Z8_’'v^fVf’•UQXj_Z8p½ÇdW7^Bu-^oŒ’•˜y^Bǖ˜Yv–’dobp £v'^fokW'~8Zv$’–^ Z5vš’–Xhu U’•ZÁn`U\‘obZfv ǖ^BWuÁXdvv'Xh_Bž²vy’dobp pBU’•U©Xh_ U—W'U8_BpB^u Z8Ç¡Ç¡Z~’'vu ^pBZQ\ (y¥k® *¿!ƒ•_ ’–gZ¨v'U8u Z HU `c v'^uHZ@^’–gBZSW v'^BiBgBXdvy’•Xh~8U’•Zpu€Z’–g^pvLc1vyob~Qg-Uv@v7Z8\sZ~’¡X«^`_-u€^kpBZS\dv ^`W—ikU’s’•ZSW¡_-u€X‘Ãf’dokW'Z%u€^pBZ8\svLc HZSW'Z _B^f’ ~8^B_v'X[pBZSW'Z'p (–¥)¤ *¿S™C^ HZn`ZSW'cfVkZ8~8Uo+vLZm’–gBZvLZ<u€^kpBZ8\dv)W'Z8\  ^`_€u€U8_  U5vvyobuÁif’–X«^`_qvLc’–gZXzW+o6v'Z?vyokžBžkZ5vy’'v u U8_  Ufvvyobu€if’¡X«^`_kv'cNvL^H’–gB%Z H~8U8_B_B^f’6VkZmo6v7Z8p€Uv.UEu:U8Xh_ v–’–W'U’•ZSž +€gZ_HU_U8\ 25Xh_BžÁ’–gZ W'Zv–oq\“’'v.^BÇ)U8_ l  ¯m¿Œ¯ gZv'ZEu€^kpBZ8\sv‡~8U8_!VkZmo6vLZ8pÁXh_?’–gZ<ÇdW'U8u "Z H^`>W #€^`ÇU?vLZS_qv'X“’•X«nkXœ-’  U8_U1\ qv'Xdv¿.

(22) HAL author manuscript. ¡ƒ _—’–gBXdvv'Xsu!oq\[U’•Xh^B_ vy’dobpcHZ©v'gB^€Zp ’–gBZªXh_BÇ¡\‘obZ_~8Z—^`Çw’–gBZ—~8gB^BX[~8Zª^ǂU8_kU8\qv7Xdv£U_kp u Z’–gB^kpvªÇ–^BW/gBUS_p`\[Xj_Bž²u€Xdvv'Xh_Bž²pBU’•U CgBZ8_AU_U8\25Xh_Bž4WLZvyob\“’'v ^ǽl  ¯(v HX“’–g%W'U8pBXh^`žBWLUSigBX[~ ^fof’•~Q^`u€Zfv ¿ . okW W'Z5vyok\“’'vLc Z5v¡ikZ8~8X[U8\s\  ’–gB^qv'Z^fVf’•UQXj_Z8p €X“’•g u?ob\“’•Xjik\[ZXsu€ifoB’•U’–Xh^B_Bc—~8US_ gZ8\ji Xh_fnbZfvy’–X‘žkU’•^BWv‡Xh_!ik\sU8_B_BXh_Bž ~8\sXh_X[~8U8\B’–W'XhU8\švLcZfv•ikZ8~8XsU8\[\  Xs_€~8g^^qv'Xh_fž:u Z’–g^pv ^`ÇXsu€ifoB’•U’–Xh^B_€U8_Bp pBU’•U US_U1\ qv7Xdv¿+lZSžkUSW'pB\[Zvv€^BÇ ’–gBZ u Z’–gB^kp ^BÇgBU8_BpB\sXh_Bž/u:Xdvv'Xh_Bž/pBU’•U ~Sg^JvLZS_ǖ^`W’–gBZ u€U8Xh_/U_U8\ qv'XdvLc v'Z8_kv'X“’¡X‘nbX“4’ €U8_BU81\ qv7Xšv‡Xdv‡ZvvLZ8_’–X[U8\f’•^Á~^`_ŒÇyXhW'u©’–gBZ W'^fVfo6v–’–_BZv7v‡^Çq’–gBZ WLZvyob\“’'v¿. inserm-00217436, version 1.

(23) C´¡´5O8´·Nµ´8P. HAL author manuscript inserm-00217436, version 1. 5¤ ¿ t2Bu:uH^_v?e.¿+€Xdv'Z8UfvLZ Ufvv'Zfv7v'u:Z8_5’!Xh_BpBX[~8ZfvQ‡U8~’•X«nkXh’3cmpBU8u USžkZ U8_p}vLZn`ZSW'X“’4q¿+]U8Xs\[\sX[ZSW'Zfv  m\hXh_!lEgZoqu U’•^B\)¤QÂB¦BzÂ6Ä¬k¾B‰B˜Y‹B¦k¿ ¬6¿ §.Z8Zm|/c &}ZXh_fVb\[U’d’6| †$¿8l gZobu€U’•^BXhp€USWy’–gfW'X“’–Xdv ¿§.U8_k~8Z’¬k®B®+¤8zŠ¦B‹b“ÂB®BŠB˜Q¤B¤5¿ Šq¿ ŽZ8\dv'^B_½H¯‡c,r_BpBZQWv'^B_ %!% c.]^kZSWv|/c±]$^BuHV`USW'pBX[ZSW€  c  ,gZSW'_B^BÇyÇE|/c±Ž6W'X[Z8p½]c Z’UQ\d¿‡¯ gkZ ru:ZQWYX[~8U8_—  ^\h\[ZSžkZ£^Ç!lEgBZoqu U’•^B\h^B8ž /iBW'Z8\[Xsu€Xh_kUSW  ~8^BW'Z1vLZ’ ^Bǀp`XdvLZ8Ufv'ZU8~’•X‘nkX“4’ —u Z8UvyokWLZv ǖ^`W W¡gZoqu U’•^BXhp USWy’–gfW'X“’•Xsv¼~8\sXh_kXs~U\’–W¡X[U\dv ¿E¯ gZ>  ^u€u X“’d’•Z8Z/^`_ . oB’•~S^Bu€Z1|1Z8UfvyokW'Zv¼Xh_ lEgZobu:U’•^`Xhp rEWy’–gŒWYXœ’¡Xsv  m\sXh_kX[~8U8\q¯)W'XhU8\šv ¿rEW–’–gfW'X“’•XšvlEgBZoqu²¤QÂBÂBŠqzŠB¾6‘‰f¬kÂB˜y¥k®q¿ ¥6¿ lZ8~8^kuÁu Z8_BpBU’¡Xh^B_v€Ç–^BW?’–gZ W'ZSžkXdvy’–W'U’–Xh^B_^ÇpfWyokžqvo+vLZ8pXj_ ’–gZ¢’–W'Z8U’–u€Z8_’C^BÇEW¡gBZobu U’•^BXsp USWy’–gŒW¡X“’•Xsv¿T<W'^fokiǖ^BW<’–gZ lZv•ikZ8~’^BÇm†‡’–gBX[~v€U8_p †(Ãb~8Z8\h\[Z8_k~8Z Xh_ªtk~8X[Z_~5Z (¡T l †±†2t *Q+W¡gBZoqu€U’•^`Xhp USWy’–gŒW¡X“’•Xsv(v7Z8~’¡Xh^B_q¿8]$W %±l$gBZobu U’•^B\)¤QÂB‹B‘ŠB‰6 ¬)¤B¤Q˜Y¦k¿ ¦k¿ ]^kZSWv)|/c`n`US_ pBZSW)™€Z8X 7pBZ|—¿eW'ZnkZ8_’•Xh^B_:^BW)W'Z’•USW'pŒU’–Xh^B_:^BÇ '^Xh_5’‡pBU8u€USžkZ?Xh_€W'gBZobu U’•^BXsp USWy’–gŒW¡X“’•XsvQwXdvvyobZfv ^ÇpBZ8ǖXj_kX“’•Xh^_c ZSnkU8\‘obU’¡X«^`_AU8_Bp4X[_’•ZSW¡iBWLZ ’•U’–X«^`_A^BÇ ik\sU8Xh_4WLU8p`X«^`žBW'UQigkv¿ÁCWyokžqv ¬k®B®f¬qz¾f¬š¤Q‰+¤Q‰B˜y¬B¥6¿ ¾q¿ tk^foBVBW¡X[ZSWE|/c H^fokžkU8pf^qvE|—¿N™C^ 4’š^UvvLZvvCZ8USW'1\  W•gBZobu U’•^`X«p USWy’–gŒW'X“’¡X[v!Xh_pBU8Xs1\ Æ~\[Xh_X[~5U\ iBW'U8~’–Xh~8Zf¿8]Zvy’6eW'U8~’6lEZ5v‡ (\jXh_!lEgZobu:U’•^`\B¬k®B®¦k–¤QÂ6“‰BŠB˜Y‹ŒÂq¿ ‰q¿ ]USW'^B_£T?c)]E^fof’–W•^B_½ƒLc(T<XzW'UobpBZ8Uo]c lUSnkUobp e.¿NlZ8ik^`Wd’–X‘_fžÆ^Ç WLU8p`X«^`žBW'UQigBX[~ u Z’–g^pvCXs_ W'US_pB^u€1X 5Z8p4~^`_5’–W'^`\h\[Z8p ’–WYX«U\dv}Uvv'Zvv'Xh_Bž-vy’–Wyob~’dokWLU\ ^foB’•~Q^`u€Zfv Xj_AW'gBZobu U’•^`X«p²USWy’–gfW'X“’–Xdv ¿¢r_B_ l$gkZobu©€Xdv)¬k®B®B¾q¿ ‹k¿ #CZSWyV`%Z #kZ Tc |1^\hZ8_fVkZSW•žgkv!T€¿N§.Xh_kZ8USW!u€X‘ÃbZ8p u€^kpBZ8\yv!ǖ^BW\h^`_ŒžXœ’dobp`Xh_kU8\(pkU’•Uf¿b„:"Z ^BW # tBiBW¡Xh_fžbZSWŒ¬k®B®B®q¿ Âq¿ §."Z HXšv %r€¿qtf’•U’–Xsv–’¡Xh~U\biBWYXh_k~8Xhi\[Zv ǖ^BW.~\hXh_kXs~5U8\’–W¡X«U\dv (yƒ' ±™@†  *`UQ_wXj_5’–W'^kpob~ ’š^`-W  _^’•ZE^B_ U_ Xh_’•ZSW'_U’¡X«^`_U\BžfobX[pBZ8\sXh_kZf¿kt’•U’q|1Z8p ¤QÂBÂBy¤8‹bd¤QÂB®BŠB˜y¥B¬6¿.

(24) HAL author manuscript inserm-00217436, version 1. ¤Q®q¿ §.Z"HXšv %rc1| U8~8gBXh_  ¿ ƒ'_’•ZS_5’–Xh^B_ ’•^ ’–WLZ8U ’š˜¡˜ CgB^ v•gB^foq\hpo6v7Z­ƒL¯±¯  ]$W %²  U8_B~8Z8W ¤QÂBÂBŠz¾‹b“¾f¥k‰B˜Y¦Œ®q¿ ¤B¤5¿ §.U8~8gBXh_ %'|—¿:tf’•U’–X[vy’•Xh~8U8\‚~8^B_v'X[pBZSW'U’•Xh^B_vXh_@’–gBZ—Xj_5’'ZQ_’•˜š’š^B˜ ’–W'ZU ’¼iBW¡Xh_B~8Xhi\[Zf¿C  ^`_5’–W'^`\   \sXs_ ¯)W¡XhU8\dv)¬k®B®B®Jœ¬)¤Œd¤Q¾B‰B˜Y‹ŒÂq¿ ¤¬6¿  ±e6| e   Çse6| e.¿+ƒ' ±™ ¯‡^`iBXh~:†,Â>tf’•U ’–X[vy’•Xh~8U8\(iBW'Xh_k~Xhik\dZvCǖ^`WC~8\hXj_BX[~5U8\ ’–W'XhU8\dv¿¯ gZ †‡okW'^BikZ8US_ rEžkZ8_B%~  ǖ^`W+’–gZm†±n`U8\“obU’•Xh^`_H^`Çq|/Zp`X[~8Xh_kU\BeW'^kpob~ ’'vE¤ ÂB‹Bz .e6|£e ƒ' ±™ šŠB¾BŠ –ÂB¾q¿ ¤QŠq¿ r\“’•u:U8_>HTcÁtk~8gob1\ Žc |/^BgBZSW:Hc†.žBžkZSW:|1cm€UnkX[pB^ǖÇÁŽNc† \‘V`^okW¡_Z½€cZ’ U8\d¿$¯ gkZ W'ZnkXdvLZ8p>  .m„‚)t .l¯ v–’•U’•ZSu€Z8_5’!ǖ^BW€W'ZSiB^BWd’–Xj_Œž>WLUS_Bpk^`u€1X 5Z8p ’–W¡XhU8\dv(ZSÃBik\[U_U’•Xh^`_/UQ_Bp/Z\[USVk^BW'U’–X«^`_b¿ r_B_!ƒ¡_’•ZQW¡_?|/ZpH¬k®B®+¤8–¤QŠf¥œ¾B¾BŠB˜¡Âf¥6¿ ¤¥6¿ ]^fof’–W•^`_‚ƒ'c)¯+oBVkU8~Sg‚Žc)T?X‘W'UobpBZUo ]cNlEUSn`Uobp¢e.¿| Z’–gB^kpf^B\h^BžX«~8U8\‡p`X[ÇyǕZSW'Z8_k~8ZvXj_ ~\[Xh_X[~8U5\ ’–W¡XhU8\dv;Zn`U8\«obU’¡Xh_fž _^`_ŒigUSW'u:U~8^\h^BžX«~8U8\/U_pikgkUSW¡u U8~8^\«^`žkXh~8U8\ ’–W'Z8U’–u€Z8_’'v;^`ǗgBXhi U8_Bp #k_BZ5Z ^qvš’•Z^UWš’–gŒW'X“’¡X[v¿ %U8u U ¬k®B®BŠ“¬kÂB®6d¤Q®B¾f¬k˜¡‰B®q¿ ¤8¦k¿ ¯)gBUSVfoB’<T?c)† v–’•ZS\h\sU’  c ]^oB’ W¡^B_ ƒ'c tkU8u Uu U‚ ,|1c.lUSnkUobp e.¿N|/Z’–gB^kpB^`\h^BžkXh~8U8\ XdvvyobZ5v€Xs_ ’–W¡XhU8\dv$UvvLZv7v'Xh_Bž iBW'Xhu USW ‚iBW'^`iBg \[UÃkXdv^`LJnkZ8_B^fo6v(’–gfW'^Bu!Vk^k˜¡Z8u!Vk^B\jXdv7uw¿`†‡okW(™€ZUSWy’ %E¬k®B®B¾“¬k‰6 ¬B¬k‰B˜ ŠB¾q¿ ¤Q¾q¿ ]USW'^B_‚TcJ]$^fof’–W•^`_wƒLcNTEX‘W'UobpBZ8Uo‚]EcqlUn`Uobp:e(¿ #!Xh^B\[U’¡X«^`_‚^BÇ ’–gZÁXh_’•ZQ_’•˜š’š^B˜ ’–W'ZU ’.ifW¡Xh_k~8X‘ik\dZ US_p©W'U’•Zª^BÇ u Xdvv'Xj_Bž pBU’•U}Xh_ v–okikZSW'Xh^`W'X“4’ —’–W¡X[U8\šv Ufvv'Zfv7v'Xj_Bž v–’–Wyob~’dokW'UQ\€^oB’•~Q^Bu€Zfv Xj_@W•gBZobu U’¡X[~ pBXsv7Z8UvLZv ¿rEW–’–gfW'X“’•Xsv+lEgZobu¨¬k®B®¦kh¦5¬š¤8‹B¦B‹Œ˜S¤8‹Œ¾¦k¿ ¤Q‰q¿  ±e6| e   Çse+| e.¿±e^BXj_5’'vÁ’•^—~Q^`_kv'X[pBZSWw^B_ªu:Xdvv'Xh_Bž—pkU’•Uf¿ ¯)gBZ †±okW•^`ikZUS_ªrEžkZ8_B%~ —Ç–^BWÁ’–gkZ †‡nkU8\‘obU’¡X«^`_€^BÇq|/Z8pBX[~8Xj_kU8\feW'^kpob~’'v)¬k®B®+¤8z ±e6| e s† &>e ¤Q‰B‰B¾ –ÂBÂq¿ ¤8‹k¿ |1^`\[Z8_fVkZSW•žBgqv(Tcq¯)gBX v±™H&c % U_kv'Z8_€ƒ'c`]Zob_B%~ #bZ8_v.  c CZ:_  USW'p!|/Tc`|/U8\[\sXh_k%~ #BW'^kp’  mcbZ’‡US\ ¿ r_BU8\ Xh_Bž Xj_k~^u!ik\sZ’•Z \h^`_ŒžXœ’dobp`Xh_kU8\q~8\hXh_X[~5U8\f’–W'XhU8\kpBU’•Uf¿8] X«^Jv–’•U’–Xsvy’•Xh~fv)¬k®B®f¥qh¦bÄ¥B¥q¦Œ˜•¾f¥6¿ ¤QÂq¿ ] okWy’š^`_£rc,r\“’•u U_ €Tc±l8^ qv–’•^`_ e)c±™C^B\hpBZSW?l §$¿.¯ gZ pBZv'Xhž_Æ^Ç!v'Xsu!ob\[U’¡X«^`_/vy’dobpBXhZfv€Xs_ u Z8pBXs~U\6vy’•U’–Xsvy’•Xh~fv¿ktf’•U ’q|1Z8p!¬k®B®B¾œ¬q¦bÄ¥B¬k‰BÂB˜¡Âf¬6¿. .

(25) HAL author manuscript inserm-00217436, version 1. ¬k®q¿ n`U_/pBZQWH™HZ8X 7pBZ w¿)™€^-’–^W'Z8U8pW'U8pfXh^BžBW'USiBgkv U8~8~5^BW'pfXh_fž’–^ ’–gBZtBgBUSW¡i [nkU8_/pBZSW!™HZX 7pZ u Z’–gB^kpq¿ %±l$gBZobu U’–^B\B¬k®B®B®Jœ¬k‰6 ¬k¾+¤Q˜¡Šq¿ ¬)¤5¿ ]$Wy)o B_Zv–’•%Z B_ Cc)nbU_£pBZSWE™HZX 7pBZ Hc ]^ZQWvE|/c n`U_ÆpBZSWE§(Xh_BpkZ8_/tc)§.Uvv'ZSWLZ |1c.n`U8_ pBZ8W #!\hZoB’•ZS_  E¿b¯ gZ¢tkgBUSW•i dnkU8_‚pZQW,™HZ8X 7pBZÁu Z’–g^p‚^fof’–˜–ikZSW¡Ç–^BWYuHZ8p ’–gZH§.USW7v'Z8_ Lt~^’[’(u€Z’–gB^kp ^B_:’–gBZ Xh_kp`X‘nbX[pobU\ikU’¡XhZ8_5’©\«Zn`Z8\>Xh_ UfvvLZfvv'Xh_BžW'U8pBXh^BžBW'USikgv Xh_ Z8USW'\  WYgZobu:U’•^`Xhp USWy’–gfW'X“’•Xdv¿ %  m\[Xs_ †.iBXhpZ8u€Xh^\k¬k®B®f¥6j¦Œ‰6‘¦Œ®f¬k˜S¤¬6¿ ¬B¬6¿ n`U_ÆpZQW?™€Z8X pBZw€cEtXhu€^k_ §.c<tku€^\[Z8_ % c<tf’–W'UQ_Bp #!cEtBgBUSW•i %c±]^ZSW7v?|/c Z’CU8\d¿+™H^ -’–^ W'ZSik^fWd’W'U8pfXh^BžBW'USiBgBX[~EpBU’•U Xh_!WLU_pB^`u€1X ŒZ8p€~8\jXh_kX[~U8\f’–W'XhU8\dv‡Xj_€W¡gZobu:U’•^`Xhp€USW–’–gfW'X“’•XsvQžfobX[pBZ8\sXh_kZv‡ÇdW'^u U W'^fok_Bp’•UVk\«ZEp`Xdv'~o6vv'Xh^_q¿5rEWy’–gŒWYXœ’¡XsvlEgBZoqu@¬k®B®f¬6œ¥k‰6Ä¬‡¤8¦Œ˜Y‹k¿ ¬kŠq¿ C\[USW'Z>v #k^`ž §.c nbU8_ pBZQW<™HZ8X 7pBZ:€c.pBZ %QUSžkZQW %'e)c.T?^okžBg£rc CU8\[pBZ8_ %c |1U\[U8Xdv7Z |1c(Z’<U\ ¿ ¯)gBZSW'UQikZoB’¡X«~½Z8ǖǡZ~’€^BÇE’–gBZ ~8^BuHVkXh_kU’•Xh^B_/^`ÇCZ’•US_ZSW'~5ZSif’HUS_Bpu Z’–gB^’–WLZÃkU’•Z ~Q^`uCikUSW'Z8?p €X“’•g/Z8U8~8g ’–W'Z8U’–u€Z8_’U8\h^B_BZEXh_!ikU’•XhZ8_’'v €Xœ’–g!W'gBZobu U’•^`X«pÁUQWy’–gfW'X“’•XdvQfpB^foBVk\hZ8˜yVk\sXh_kp!W'US_pB^u€Xdv7Z8p€~8^`_5’–W¡^B\h\[Z8p?’–W¡X[U\ ¿ §.U8_B~8Z’+¬k®B®f¥qzŠB¾BŠ6œ¾B‰¦Œ˜Y‹6¤5¿ ¬B¥6¿ n`U_ pBZSW>™HZ8X 7pBZ Hc¼§.U8_pB"Z €Z@lEc !\[USWLZv #k^Bž4§.c lE^kpfW¡X‘žfob$Z 5$˜ #CU\‘nbZSWLpBZ #!ctkZ’[’•Uv>§.c eZ8pBZSWvLZS_ÁlcqZ’‡U8\d¿eW'ZvLZ8_’•U’–Xh^B_ U8_BpwU8_BU8\ bv'Xdv ^BLJpBU’•U?^B_€W'U8pBXh^BžBW'USiBgBX[~?^foB’•~Q^`u Z?Xh_w~8\[Xj_kX[~8U8\’–W'XhU8\dvQ ZÃikZSW'XsZ8_~8Z<ÇdWL^u©’–gBZE¯+†±|£e . vd’dobp b¿frEWy’–gfW'X“’–Xdv+lgBZobu@¬k®B®¦kj¦5¬ ¥kÂB˜¡¾B®q¿ ¬q¦k¿ n`U_HpBZSW+™€Z8X pBZmHc !\[USW'Z5v #k^BžH§.cfl^pfW•X‘žfob%Z 5$˜ #CU8\‘nbZSW7pBZ #!ck  ^p5W'Z8US_5ow  cf]^`\h^qv'X“o€™Hc|1Z\«^˜ T^`u€Zfv % c!Z’ U8\d¿$ m^ku!ikUSW'Xdv'^B_©^BÇwZ’•US_BZSWL~8ZSif’ U8_Bp u Z’–g^’ W'ZÃ`U’•Z8cU\«^`_Z>U8_Bp—~8^kuHVkXh_kZ8pBcXj_ª’–gkZ ’–W'Z8U’–u€Z8_’ ^`ÇW¡gBZoqu U’•^BXhp:UQWy’–gfW'X“’•XdvQ3’ €^B3˜ BZ5USW.~8\hXj_kX[~5U\JUS_Bp€W'U8pBXh^`žBWLUSigBX[~EW'Zv–oq\“’'v.ÇyWL^u ’–gZ?¯+†‡| e . vy’dobp ckUEpB^oBVk\«Z8˜yVk\sXh_BpBcBW'US_pB^u€X Z8p?’–W¡X[U\ ¿frEWy’–gfW'X“’–Xdv+lgBZobu ¬k®B®B¾j¦5¥d¤Q®B¾BŠB˜¡‰f¥6¿ ¬k¾q¿ ™oq\[v'u:U8_qv ™?|1c %U5~8^fVqv %&—c+nkU8_¼pBZSWm™HZ8X 7pBZH|/c+nkU8_ r\‘VbU8pBU8˜ EobXjikZQWvETrc(t~8gZ_ # Cc ]EX 7\šv'u  U %&@¿C¯±gBZ—~8^fokWv'Z—^ǂW'U8pBXh^\«^`žkX[~ pBU8u USžkZ pokWYXh_Œž ’–gZ Ç¡XhWv–’ v'X‘à `Z8USWvÆ^`ǼW¡gBZobu U’•^BXsp USWy’–gŒW¡X“’•Xsv¿ŒrEWy’–gfW'X“’–Xdv+lgBZobu@¬k®B®B®Jœ¥kŠ6d¤QÂf¬k‰B˜y¥k®q¿.

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