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Early mortality among adults accessing antiretroviral treatment programmes in sub-Saharan Africa.

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(1)Early mortality among adults accessing antiretroviral treatment programmes in sub-Saharan Africa. Stephen Lawn, Anthony Harries, Xavier Anglaret, Landon Myer, Robin Wood. To cite this version: Stephen Lawn, Anthony Harries, Xavier Anglaret, Landon Myer, Robin Wood. Early mortality among adults accessing antiretroviral treatment programmes in sub-Saharan Africa.. AIDS, Lippincott, Williams & Wilkins, 2008, 22 (15), pp.1897-1908. �10.1097/QAD.0b013e32830007cd�. �inserm00266588�. HAL Id: inserm-00266588 https://www.hal.inserm.fr/inserm-00266588 Submitted on 17 Jun 2010. 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.  

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(10) mlO›|–€l!qN€—f§vˆ– €—L²Ql fqNŸHz8b:c g ­ C‡ zN€s’cOqNl.fz fWlˆ¢z8œ fybC,{°nW€ch‚’¢OlOŠc±€—fh¿lOŠlon€ n€ƒbCep‰ zzNcOl:ŠŒ{W¢OŠ€—f €¢!l Šz8œb:¢z›cy‚ Ñ °D·  Oi ~|€s‰ eŠ—c‡cOŠ‚z ¡ bCRcOlLbC›cOfybߢz›|d Š€lOf¢cˆlf ‡ €—RzŠ—z ‰ €—¢lOŠB‚Cœ ddRcy‚Q‚R€—zNfel‡ cš–c!c fWlO¢Oe€c‡ cO§€—f|– z8bCe|ez ‚d €ƒb:lOŠ—°–l‚RcOlOf¢OzN››hœf€ƒbC{ ° – l8‚’cO|dRz ‰’l››c‚¸° &&  iO£c¦b:lO°l.flOŠs{ ‚Qcy‚*z ¡0lLb:l©¡Rz ›@bC’cOlAbC›Wc fbߢOz ez8bR‚ßelo‡cˆ¡Czœ f bCelLbNbCecˆc ¡C¡C€¢lO¢{WzN¡0v • ™*qNl‚9Rc¡CŠcO¢ob:cOh–{RlLb:cy‚9z¡B‡ €—RlOŠ Š—z lO‚,œ ddRcy‚Q‚R€—zNflOf§ŸPgpÞ<¢OcOŠ­Š ¢Oz8œ fybS’cO¢Oz8‡ c,{qN€‚‚R€—›<€Šl*lO›zNf1‰§d lLbC€—cOfybR‚0bCRc!lAb:cO|€—f|e€—‰ e°€—f ¢OzN›cˆlOf|Rc‚Rz8œ R¢OcO°,Š—€›€ƒb:cO ‚RcLbbC€—f8‰S‚ & Î q &.Ó iv • ™`ely‚0– ccOfcO›zf ‚,bCRl¦b:cO±bzh– cˆlˆ¢Oz ‚b:°c¡C¡CcO¢ob:€Œ‡ c±€—fb:c,‡cOfybC€—zf€—f. Ó.

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(12)      !#"%$ Rcy‚’zœ ’¢OcO°,dzz *‚RcobbC€sf8‰S‚ & Þ ° &.Ñ i¤ œ ,bCec.›zRcOqv • ™ànl‚*cy‚,b:€—›<lob:cO±bz§elL‡ cˆl‡ cCb:cO Î Ï1Òq—ÒÒÒ° Ó Ï1Òq—ÒÒÒ|cOl¦bCeN‚*€—fŠ—zn lf›€Šcˆ€—f¢Oz ›ch¢!zœ fb€—c8‚*€—f|Î ÒÒNÏplOŠ—z fc & ¹  i gWcy‚d €ƒb:cšbCec‚Rc©d z ‚R€ƒb€s‡ c±¡C€—f  €—f‰ ‚Rq lob:l©¡Rz›@bCec©’c‰N€Œz f‚Cœ ‰‰ c8‚,b bCelobVcOl:ŠŒ{<›z,b:lŠ—€ƒbC{ HAL author manuscript. Rlob:c‚*l›zf8‰<lOyœŠƒbR‚*€—f§v • ™6dRz ‰1RlO››c‚*lRc©e€—‰ e  & Î  q ¢zfyb®€s–8œb:€—f8‰|bCzj‚,œ– ‚Cb:lfyb:€—lOŠ. inserm-00266588, version 1. ™9e€‚l flOŠ­{ ‚R€‚*¡Cz8œ fpbCelobßcOlŠs{›Wz ,b:l.Š­€Žb,{<¡CzNŠ—Š—z8n€—f‰€—f€ƒb:€lob€Œz fz¡Sv • ™ànly‚m‚Rc‡ c’l ŠŒ°’¡Cz Š. Š—z ‚L‚Rcy‚*€—fz8‡cRlOŠ—ŠNd lLb€—cOfb0’cAb:cfbC€—zf  & ·  i ™9ec©v • ™*°k®³Ÿ£¢OzŠ­Šl– zRl¦bC€—zf¢OzN›|d l.RcO z8œ8b:¢.z ›c8‚*¡Rz› & ·xv • ™`d:z‰Rl››<c‚*€—fŠ—z8nc’°’€—f¢Oz ›<ch‚’cobbC€—f8‰ ‚ , d’cOz ›€—f lOfyb:Šs{€—f vx¡D€¢l 0 n€ŽbCehbCez ‚Rc©€—f & Î|~pž ¢Ozez8b*‚bœ8€—c8‚P¡’z ›@µ*œ Rzd c©lf±³<zbCe|vx›cR€¢Ol & Î  i e€—‰Nec*lO›zf8‰d lob:€—cOfybR‚*€—f|Rcy‚’zœ R¢!cO°,Š—€›<€ƒb:cO‚RcobbC€—f1‰ ‚*¢Oz›|d lRcOhbzpbCelobÚz ¡Sd lob:€—cOfybR‚SbCRcOl¦b:cO €—fe€­‰ e°€—f ¢OzN›Wch‚RcobbC€—f8‰ ‚’qNcL‡c fWl ¡b:c.*lO¦²,œV‚,b:€­f1‰¡Cz0– ly‚’cOŠ­€—f cˆ€›<›Wœfz cO¡,€¢O€cOf¢{  & Î  i ~€s‰ e›z,b:lŠ—€ƒbC{|RlLb:cy‚9el‡ cˆl Š‚’zW– c!c fpRcd zb:cOh–{€—f €s‡ €yœlOŠ¢OzezbR‚9€—f‚CœN– °¦a le lRl.f vx¡D€¢l8i1™9z§‰ l€—fl©‰’cOlob:cSœ fc¦‚Cb:lf€—f8‰<zN¡ bCe€‚9d’zy– ŠcO›q8nWc©Rc‡ €cLn@bCecˆ›zb:l.Š­€Žb,{’lob:cy‚Rq b:c›|d zRlOŠ €‚CbC€s–8œb:€—zfq€‚¡Cl!¢ob:z Q‚*lf¢OlLœS‚Rcy‚*z¡VclobCelO›zf8‰<lOyœŠƒbVd lobC€—cOfybR‚*l!¢O¢Ocy‚Q‚R€­f‰ v • ™`dRz‰Rl››<cy‚*€—fj‚,œ – °¦a le l’lfvh¡R€¢lˆlf¢OzfN‚R€®c9dz ‚¦‚R€s– Šch‚,bCRlLb:c‰€—cy‚0b:zlO8’cy‚¦‚ bCe€‚Ai Æ  Å.Ë×ÇRÙQÅ 8 ÙRÆyâ  ÉSʴǦƁÆOË.ÙÄÉ´ËÅ — ÙRÆOÅ   ˜ ch‚QcOlR¢Oec!pµmf8‰ Š€‚Re°’ŠlOf8‰8œl.‰ c©d8œN– Š—€¢lobC€—zf ‚P€—fhIµgxk*³Wµ q8œS‚€—f8‰|bCecšb:c.›‚ !l fb€ RcobCRz8‡€s’l Š  q o~vxv. • ™

(13). q Ov • ™

(14). q Ovx¡R€¢Ol qO›z,b:lŠ—€ƒbC{ q OcOlLbCe i a cOlR¢ec8‚0nc.Rc. ¢Oz›|d ŠcLb:cOhœ dhbCz|gcO¢!c›|– c9Î ÒÒ¹hbCz|€—cOfb€—¡,{pd8œN– Š€‚¦ecO|Rcd zbR‚9¡’z › z8– ‚’c‡ lob:€—zflOŠ v • ™Õ¢OzezbR‚9€—f‚,œ – °¦a lOel.RlOf|vh¡CR€¢Ol8ÝybCezڂ’c©RcdzbC€sf‰zf‚,œ ,‡ €s‡lOŠ dRz dz bC€—zfN‚*z8‡ c.0bC€­›<c lfpbCezڂ’cˆcy‚R¢.D€s– €—f‰|bCech‚:d cO¢obC,œ › z¡V¢OloœV‚Rcy‚*z ¡0c!lobCehnWcRch‚RcOŠ—c!¢ob:cO ivx €ƒb:€—zflOŠ l,bC€Œ¢ Šcy‚Vnc’c±€— cOfybC€—¡€cO¡RzN› RcO¡CcRcOf¢Oc8‚P€—f|d8œ– Š€‚Re cy|d ld c.¦‚*lf§lL–S‚,bCRlO¢LbR‚9¡Rz› ›l²Rz €—fyb:cRflob€Œz fl Š vˆ,g}a¢!z f¡Cc’c f¢cy‚*€­fxbCec©dRcO¢!cO €—f‰ & ΛzfybCe ‚LiO¤Vz*¢zez8bR‚0np€ƒbCe›|œ Šƒb:€sd Šc dRcy‚’cfyb:lLbC€—z f ‚z ¡V›z Cb:lŠ—€ƒb,{Wlob:lˆ¡Rz›  €—¡¡:cRcOfybbC€­›<cˆd cR€—z N‚RqybCecˆ›z ‚,bS’cO¢Ocfb0’cdzbnly‚. Þ.

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(16)      !#"%$ œS‚Rc! i gWlob:l©¡Rz› ¢OzfybC:z Š—ŠcO¢OŠ­€—f €¢ylOŠ8bC€lOŠ‚0nWcRc©fz8bS€—f¢OŠsœcO€­fxbCecˆly‚L‚’cy‚L‚R›<c fbVz¡ ›z,b:lŠ—€ƒbC{Rlob:c‚*ly‚0bCecy‚Rcˆlob:lˆl.Rc œ fŠ—€— cOŠ­{|b:zh– c©‰ c.fcORlOŠ—€­Ì l!– ŠcšbzpbCech‚R¢OlOŠ—c!°œ d<z ¡Vv • ™ ‚Rc.,‡ €¢yc‚P€—fhbCec©‰ cOfcRlOŠd zd8œ ŠŒlob€Œz fiNa8œ›§›<l{Wcy‚,b:€—›jlob:c‚9z¡ bCec©el.ÌlR|RlobC€Œzڂ*¡CzBbCec HAL author manuscript. ly‚Q‚Rz ¢ €Œlob€Œz fz¡VcOlRŠ­{W›z Cb:l Š—€ƒbC{xn€ƒb:eŸPg|Þ<¢Oz8œ fybßlfpnW€ƒbCelO8‡ lOf¢!cOW˜£~Í ‚,b:l‰ cšnWly‚. inserm-00266588, version 1. gWlob:l©¡Rz› & ·hd8œ– Š€‚RecO¢Ozez,b9‚bœ8€cy‚*¢Ozfyb:lO€—f€—f‰ Ó ¸q®Ï ÓÑ d l¦bC€—cOfybR‚0bC’cOlAb:c!h€—f¢Oz8œ fybC€cy‚. ¢Ozfyœ¢ob:c!pœS‚:€—f8‰<l©RlfzN›°cO¡C¡c¢obR‚9›WzNcOŠ  & ¸  i. 8ÙRÆOÇ ÉSÊjÙRÆ´ÈBÄÅÊ  ÇDÙQÅ  SØ ÙÄÉ´Ä´ÄÅoÙ   ­ÙC⠀—fhn<cy‚Cb:qNc!ly‚,bVl.f‚Rz8œ8bCecfvh¡R€¢OlOfl’ch‚,œ›§›<lR€‚QcO|€—f™*l!– Šc & i ¯ lobC€—cOfybR‚0nWcRc©›Wl €—f Š­{ RcO¢!c €s‡ €—f‰d8œ– Š€¢h‚QcO¢ob:z8SbRc!lobC›cOfybQi™0nc.ŠŒ‡ cˆzN¡ bCecˆ¢Oz8ez CbR‚BnWcRcš– ly‚RcO€—fhœ ,–lOf‚RcLbbC€sf8‰S‚ lf Ñ nWcRc©,œ ’lŠi1™ec±›c! €lOf|– l8‚RcOŠ€—f cˆŸPgpÞ¢!c Š—Š¢Oz8œ fybV€—fhbCecy‚’ch‚,bœ€—c8‚9Rlf1‰ cOW– cobnWcOcf Þ Ó lf & Þ ¹¢OcOŠ—Š‚ 1k‘lOfpbCec±›WcO €lOfyœ RlLbC€—z fWzN¡0¡CzNŠ—Š—z8nW°œ dRlf8‰ c!W– cLbncOc.f Ó lf|Þ Ñ ›zNfbCeN‚Ai8™9ecš‡ly‚CbV›l²RzR€ƒbC{z¡ bCecy‚’c©d lob€Œc fbR‚0nWcRc©v • ™P°CflO€s‡cˆlf›zڂCb9€—f€ƒb:€—lob:cOhbC€ dNŠcO° 8,œ ‰hbCecRld{xbCelobV€—f¢Ozd z8Rl¦b:cO±bnpzfyœ¢OŠ—cOz ‚R€—cˆlOflOŠ®z ‰8œcy‚lfl©fzf°Cfyœ¢OŠcOzڂR€c©RcL‡ cL‚Rc bCRlf ‚R¢R€sd8b:l‚Rcˆ€­fe€s–€ƒb:zLi ¥<‚R€­f1‰dRzNyœ¢LbC°,Š—€›<€ƒb9›WcobCez N‚Rq8bCec & Î °,›Wz fbCe‚,œ ,‡ €s‡ÚlOŠdRz dz bC€—zf€­fpd lobC€c fbR‚0npez nWcRc©fz8bSŠ—z ‚,bbCz|¡CzNŠ—Š—z8n°œ dRl.f8‰ cOh– cLbncOcOfÒ iŽ¹8Þ<lf Ò iŽ¸8Îq8n|€ŽbCehbCec©‰Rc!lob:cy‚bS–8œ RcfWz ¡ ›z,b:lŠ—€ƒbC{<z ¢O¢oœ €—f1‰yœ R€—f8‰|bCec±€—f€ƒb:€l Š›z fbCe ‚*z¡Bv • ™  ™*lo– Š—c & Ai ~WcAb:c.z‰ cfcO€ƒbC{€—f z8œ8b:¢.z ›c8‚0– cobnWcOcOf|dRz‰8RlO››<cy‚*›l{pRcO¡,Šc¢obߏ8€—¡,¡:cRcOf¢Oc8‚P€—f|– z8bCeh– ly‚RcOŠ€—f c©d lobC€cOfyb ¢elRlO¢ob:c.D€‚,b:€—¢8‚*lOf|dRz‰8Rl››<cˆ¢Oel’lO¢ob:cR€‚Cb€—¢8‚Î Ò  i a8œ ,‡ €s‡ lOŠdRzd z bC€—zfN‚0nWcRc Rcd z8b:cOl¦bB– zybCe & Îlf|ÎÞ›zfybCe ‚*z ¡V¡CzNŠ—Š—z8n°œ d<€—f¸‚Cbœ8€—cy‚*lOfhbCecy‚Rch‚ReznWcOhbCelob ›z,b:lŠ—€ƒbC{<lO¢O¢.,œ €—f‰<€­fxbCech‚Rc!¢Oz fW{ cOl*z¡Bv • ™ nWly‚9›|œ¢OeŠc‚L‚0bCelfxbCelobV€—fhbCecˆ¡C€sL‚,bQi kmzf8‰ €ƒbœ €—fl Š¢OelOf8‰ c8‚*€—f›z Cb:lŠ—€ƒb,{pRlob:c‚0nc.Rcˆ¢OlOŠ—¢oœŠlob:cO§€—f‚’z ›<ch‚Cbœ8€—c8‚Î & °,Î Ó i fl|a z8œ8bCe|vx¡R€—¢lOf¢OzezbqybCec©Rl¦b:c©€—fhbCec©¡C€—¦‚,bVÞ›zfybCeN‚z ¡Vv • ™ànl‚ & ¸ i & c!lobCeN‚  & ÒÒ d c¦‚’z f°,{c!l¦‚  & ÒÒ ¯ À‚ Rq cO¢’cOly‚R€—f8‰|b:z|ÎSiŽ¸|cOl¦bCeN‚ & ÒÒ ¯ À‚0– c{zNfWÞ<›zfybCeN‚l f & i Ó. Ï.

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(18)      !#"%$ cOlobCe ‚ & ÒÒ ¯ À‚0–c{zNfzfc©{cOlÎÎ  i v ‚R€—›§€Šl9d lbb:cfpz¡0›z,b:lŠ—€ƒbC{hnWl8‚*z8– ‚Rc.’‡ cO§€—f lfzbCecHaz8œ8bCe|vx¡R€¢!l fW¢Oz ez b  & Ò  .l f|€—fW– zbCe<‚,bœy€c8‚9RlLb:cy‚9z¡ ‡ €—RlOŠNŠ—z lO‚,œ dd’cy‚L‚R€—zNf. SÞ ÒÒ¢Oz d€Œcy‚C›<Š nWcRc©e€—‰ e V¸ Ó lf9·1¸  & Ò1q8ÎÎ  Oi fzybCec‚bœ8€—c8‚Rqez8ncL‡ cRq HAL author manuscript. ‚,œ–S‚Cb:lfyb:€—lOŠ ›z Cb:l Š—€ƒbC{WlO¢¢,œcOh– cLbncOcOf & Î<lf|ÎÞ›<z fbCeN‚*z¡0¡Cz Š­ŠŒznW°œ d  Î Ó q8ÎÞ  i £zb:lŠ—€ƒb,{pRlob:c‚P€—flˆ¢!z ez bS€—fja cOfc‰ lOŠqN¡Cz*co¾ lO›|d ŠcOq nWcRc & ÎSisÏq Ñ i Ñ lf|ÞSisÏ cOlobCe ‚ & ÒÒ ¯ À‚*€—fhbCecˆ¡,€—¦‚Cb:qڂ’cO¢OzflfpbCe€ RW{cOlQ‚z¡ bCRcOl¦bC›cOfybVRcy‚:d cO¢obC€s‡ cOŠ—{ Î Ó i8™9ec e€—‰Nec*›z Cb:lŠ—€ƒb,{pRlob:c‚0– c{zNfhbCec±¡C€sL‚,bS{cOl*z¡0v • ™Õ€—fhbCec‚Qch‚,bœ8€cy‚*›€­‰ eybS– c. inserm-00266588, version 1. co¾dNŠlO€—f cOW–{ŠŒznWc9Rlob:c‚*z ¡ ‡ €s’zNŠ—z‰N€—¢!l ŠS‚,œ dd’cy‚L‚R€—zNf<lf§l‚¦‚Rz ¢O€lob:cO|dzz €›<›|œ fzNŠ—z‰€¢!l Š’cO¢Oz8‡ c{ q ¡Cz *co¾ lO›|dNŠcÎ Ó qÎ Ï  i flOŠ—Š Î Ò§¢!z ez bR‚ : ™Plo– ŠŒc & R qybCecˆ›zb:lŠ—€ƒbC{dRzdzbC€—z f ‚*lob & ΛzfybCeN‚z ¡V¡CzNŠ—Š—znW°œ d. ,Rl.f8‰ ch·

(19) °BÎ Ñ 9co¾ ¢OcOcOcOv • ™P°k*®³ŸX‚,œ››<l{›z,b:lŠ—€ƒbC{<cy‚Cb€—›<lob:cˆz¡ Ñ i#Þ ¸NÏ

(20) Ÿ Ï i & °¹ iŽ¹.  & Î  i ™9ec©v • ™P°k*³Ÿ£cy‚CbC€­›<lob:cšnWly‚*c.D€s‡ cy|¡Rz › Þ q®· & Ò|d l¦bC€—cOfybR‚9’cO¢OcO€s‡ €­f‰. v • ™ –cobnWcOcfpÎ ÒÒ & l.f|Î ÒÒ8Þ€—f|Rc‚Rz8œ R¢OcO°,Š—€›€ƒb:cO‚QcobbC€—f8‰ ‚*lOf€—f ¢ ŠŽœNcO Ó qsÞÞ ¸|d lAbC€Œc fbR‚ €—fj‚,œ – °¦a le l’lfvh¡R€¢l8iNa€—f ¢OcšbCecfq8bCec’c©ely‚9– c!c fWl±›zRcšbCelf & Ò°¡Cz ŠŒ§€—f ¢RcOl8‚’c±€—fhbCec fyœ›|–c9d lobC€—cOfbR‚9RcO¢OcO€s‡ €—f‰v • ™Õ€—fhbCec©’c‰N€Œz fhnpez ‚Qcˆz8œ8b:¢.z ›c‚Pel‡ c©– cOcOf|d8œ – Š—€‚Re c! i ™9ecˆ¢oœ ’cfybVŠ—€ƒb:cRlLbœ Rc©€—f¢OŠsœcO§€—fhbCe€‚9Rc‡ €conª‚,œ ‰‰ c8‚,bR‚SbCelobV¡œ ,bCec0œ d l¦b:cO ¢OzŠ—Šl– z RlLbC€Œ‡ cˆlOflOŠ­{‚Rc8‚*›§€—‰ eyb*‚ezn lh‚,œ–‚,b:lfb€—lOŠŠ­{e€—‰ ec*cOl.DŠs{<›z,b:lŠ—€ƒbC{|’lob:cšbCelf €—fN€Žb€lOŠŠ—{cR€s‡cO¡RzN›@bCecˆz8:€s‰N€—f lOŠ v • ™*°k*³<Ÿ^¢Oze zbR‚Qi Æ     ­Ù,â}Ä´Ä ÅoÙ —Ù,â}Ê8Ù  ™9ecRcˆ›l{– cˆlšb:cfcf¢{<¡CzP›zb:lŠ—€ƒb,{pRlob:c‚P€—fhbCec©d8œ– Š€‚Rec!§Š€Žb:cRlobœ RcbCzh– cˆŠ—z8nc. bCel.fhbCez ‚Rcˆz8– ‚’c,‡ c!§€—f›zڂCb9Š—l.‰ cO°D‚’¢OlOŠcˆv • ™`dRz‰8:lO››c8‚0bCelobVelo‡ cOf Œ bVd8œ– Š—€‚RecOhbCecO€s lob:lš– cO¢OloœS‚’cˆz ¡9‚RcOŠc¢obC€s‡ c©Rc.d z bC€—f8‰¡’zN›@ncOŠ—Š°,,œf|v • ™`dRz‰Rl››<cy‚*€—fhœ – lOf‚’cobbC€—f8‰ ‚ n€ƒbCe›zRc©€—fyb:cOf ‚R€Œ‡ch‚’c‡ €¢OcˆcOŠ€s‡c{lOf§¡Ccnc.9Rcy‚Rz8œ R¢Ocˆ¢.zfN‚,bC’l€—fybR‚Li1™9ecˆ¼yœlŠ—€ƒbC{<z¡ ›z,b:lŠ—€ƒbC{<lob:l©€‚0œ f ¢OŠcOl*€—f‚RzN›Wc©Rcd zbR‚QÝ8›z,b:lŠ—€ƒbC{<€‚PŠ—€— cOŠ­{|b:zh– cšœ fcRc‚,b:€­›<lob:c!pbzl. Ñ.

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(22)      !#"%$ c‰Rc!cš–{›zB‚Cb9¢.zezbR‚*yœcPbz§›€‚R¢OŠl‚Q‚R€¡C€¢ylLb€—zfz¡ œ fl8‚R¢Oc.,b:lO€­fcO|d lobC€—cOfybߏcOlLbCeN‚*ly‚ Š—z ‚¦‚Qc‚0bCz¡CzNŠ—Š—znW°œ d C i8™9ec©‰’cOlob:c bCecˆŠ—z ‚¦‚0bz|¡CzNŠ—Š—z nW°œ dRlAb:cbCec©‰Rc!lAb:c bCec©d zyb:cfybC€—lOŠ ¡CzP›€‚R¢OŠl8‚¦‚R€¡:€¢!lob€Œz f ‚Li • lLb:cy‚*z¡0Š—z ‚¦‚0bz§¡CzŠ—Š—znW°œ d<€­¡C¡:cRcO|‰RcOlLbŠs{|– cobnc!c f<‚,bœ8€cy‚Rq HAL author manuscript. Rlf1‰N€—f‰|– cLbncOcOf|Î l.f|ÎÞ , ™*lo– Šc & * lfpœ f1RcO¢zRcOh›z,b:lŠ—€ƒbC{Wl ›WzNf8‰|bCec‚Rc d lobC€—cOfbR‚P›Wl!{§z fŠs{– cˆcob:c!¢ob:cOh–{€—fyb:cf ‚R€s‡cˆlO¢LbC€Œ‡ c±¡’z Š—Š—z8n°œ d  & Î q Î Ñ °,Î ·  i ™9ecˆcO¡C¡€¢OlO¢{ z¡0l!¢obC€s‡ cˆ¡CzNŠ—Š—z nW°œ d›l{|‡ l{<¢OzfN‚R€cRl– Š—{|–cobnWcOcf¢OzezbR‚*lfcob:l.€­Š‚*¢!z f¢OcRf€—f‰WbCec €—fyb:cOfN‚R€Žb,{<z¡Sd lob:€—cOfyb bCRl!¢€—f8‰<lRcˆ€—f¡¦c!¼yœc fbŠs{pRcd zb:c! i. inserm-00266588, version 1. vxflOŠ­{‚¦€‚*z¡ bCecˆ¢e l’lO¢ob:c€‚CbC€¢‚*z ¡VŠ—z ‚L‚Rcy‚0b:z|¡CzNŠ—Š—z8nW°œ d›l{pdRz8‡ €cˆ€—f ‚R€s‰ eybR‚*€—fyb:zhbCec RcOŠ—€l!– €Š—€ƒb,{§z ¡SdRz‰Rl››<c±›Wz ,b:l.Š­€Žb,{<lLb:l8iyv • ™I¢Oz ez8,bR‚V€­f}aNz8œbCe|vx¡R€¢!l fWlfŸHzb:c!° g ­ ,‡ zN€sRcˆv • ™ n€ŽbCe|‰ zzNly‚’¢Oc,b:l.€­f›<cOfybBz ¡Vz8œ8b:¢.z ›<cy‚*¡Cz8œ fhbCelobSnpec’cOly‚*›z ‚,bߏcOl¦bCeN‚ z ¢O¢oœ Rc!h€—fhbCecˆ¡,€ o‚CbV›z fbCe ‚*z¡Bv • ™Õ€—f|d lobC€—cOfybR‚Vn€ƒbCehbCec±Š—z8nWcy‚,bS– l‚RcOŠ€—f cˆŸPg|Þ<¢OcOŠ—Š ¢Oz8œ fybR‚’q Š—z ‚¦‚’cy‚0bz§¡CzŠ­ŠŒznW°œ d|nc.Rcˆco‡ cOfŠ—{< €‚CbCD€s–1œb:cO|z8‡ c0bC€—›<cˆlfhnWcRc©fzbßly‚Q‚Rz ¢€—lob:cO n€ƒbCeWŸmgpÞ<¢OcOŠ—Š ¢Oz8œ fybR‚ , ·1q ÎÎ  i ™9eyœS‚Rq€—¡Vl©dRz ‰’l››jc©Rcd z8bR‚*l©e€s‰ eŠ—z ‚¦‚0bz§¡CzŠ­ŠŒznW°œ d Rlob:cH€—fhbCecˆ¡,€—¦‚CbV›z fbCe ‚*z¡Bv • ™ÕlO›zf8‰d lobC€—cOfbR‚0n€ƒbCehbCec±ŠŒznWcy‚,bS– ly‚RcOŠ€—f cˆŸPgpÞ¢!c Š—Š ¢Oz8œ fybR‚’qybCe8€‚*›l{§– ch‚,œ ‰‰ c8‚,bC€s‡cˆz¡Se€­‰ e|RlLb:cy‚9z¡ œ fl8‚R¢OcCb:l€—f cOcOlobCeN‚*€—fhbCe€‚9d cR€—z  i É  ÈSÅ.ÄNÅ. .  àÆ ´Ä ÅoÙ  —Ù,â}ÈBÅ Ä ÅšÙ’Ä.   É — Ù 8Ù Ä8É. žpc{|e€—‰ e§›Wz ,b:l.Š­€Žb,{’lob:cy‚9Rc!¢zRcOyœ:€­f1‰|bCecˆ€­f€Žb€lOŠN›WzNfybCe ‚*z¡Sv • ™Õ›l{pRcO¡ŠcO¢obßl e€—‰Ne›z,b:lŠ—€ƒbC{pRlob:cˆlO›zf8‰€—f €s‡€yœlOŠ‚0nezl’cˆcŠ—€­‰ €s– Šcˆ¡Cz 9v • ™à–8œbVelo‡ c%{ cob bz ‚b:lb bCRcOl¦bC›cOfybQi™9e€‚*€­f¢OŠŒœc8‚*€—f€s‡ €yœlOŠ‚*cOf8RzNŠ—ŠcO€­fW¢OlQcšn|ezl’cˆlonl.€ƒb€—f1‰WbC’cOlAbC›Wc fbßly‚ nWc Š—Šly‚0bCezڂ’cˆc Š‚Rcnec.Rc±€—fhbCec©ecOlOŠƒb:e¢Ol.Rch‚{ ‚Cb:c › lnWlO€ƒb€—f1‰§’c ¡Cc.RlOŠ8b:zh~|žXb®RcOlobC›cOfb ‚Rc.,‡ €¢yc‚Li ™0nz¢.z ez bR‚9€—fja zœ1bCe|vx¡D€¢Olˆel‡ c©Rcd zb:cOxzfcOlob®eN‚*z ¢O¢oœ R€—f8‰<€—fhbCecˆ€—fyb:c,‡ lOŠ – cLbncOcOfc.f8RzNŠ—›<cOfybVz¡Sd lobC€cOfybR‚9€—fyb:zhbCec©v • ™6dz‰RlL››<cˆlOf€­f€Žb€lob:€—zfz ¡ bCRc!lAbC›cOfb Î & qÎÎqÎ ¸  Oi :f±bCecˆŸšl.d cˆ™Pz8n|f<‚,bœy{qbCe1€‚P€—fb:c,‡ lOŠSz¡VlddRz8¾ €—›lLb:c Šs{ Ó Òl!{‚9d cR›€Žbb:cO . ¹.

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(24)      !#"%$ bCez:zœ ‰e|€—f8‡ c‚CbC€s‰lobC€—zflOfhbCRcOl¦bC›cOfybßz¡0¢!z €—f¡:cO¢ob:€—z f ‚*lOf|dRcd l.RlobC€—zfz¡Bd lLb€—cOfbR‚P¡Cz v • ™Pq8bCec©›Wz ,b:l.Š­€Žb,{pRlob:cˆ€—fhbCe€‚*€—fyb:c,‡lOŠ8nWl8‚0‡ c{<e€—‰e  ldd’z¾ €—›<lob:cOŠs{ Ó Ò cOlobCe ‚ & ÒÒ ¯ À‚ Ai gWcOlobCe ‚*zN¢!¢oœ €sf1‰€—fhbCe€‚H‚RezbVd cL€zNplO¢O¢Oz8œ fyb:cO|¡Cz Ñ ¹. z ¡VcOlobCe ‚. HAL author manuscript. n€ƒbCe€—fhbCec±¡C€—¦‚,bSbCe1RcOc©›zfybCe ‚P¡’zN› dRz‰Rl››<cˆc f1Rz8Š›<cOfyb  Î &  ia€—›€ŠlRŠ—{q €­fxbCecš¤SRc!c. inserm-00266588, version 1. ¡Cz9v • ™Õ€—f€ƒb:€lob:€—z fWlfhbCecšbC€—›<cšb:l cfxb:zWd’cd lRcHd lobC€—cOfybR‚0bz‚,b:lLbVŠ—€—¡cO°Š—z f8‰|bCRcOl¦bC›cOfyb. a8b:lAb:cw¢Ozez8b:qN·1¹. z¡VcOlobCe ‚*zN¢!¢oœ RcOl›Wz f1‰§d lLb€—cOf8bR‚9d1€—zBbz§v • ™`€—f€ƒb:€lob€Œz f Î ¸  i. ™9eyœS‚Rq €ƒbV€‚*Š—€— cOŠ­{xbCe lobßco‡ cf<‚Rez,bVcŠl{ ‚*€—fv • ™Õ€—f€ƒb:€lob:€—z fWlRcˆly‚Q‚Rz ¢ €Œlob:cOhn€ƒbCe ¢OzfN‚R€cRl– Šc©dRcO°bCRcOl¦bC›cOfybߛzb:lŠ—€ƒbC{R€‚ÂSi1™eœS‚Rq cŠl{ ‚*€—f|d lLbC€cOfb0’c¡CcRlOŠ—q8nWl €Žb€—f8‰<Š—€‚CbR‚ lRc©Š—€— cOŠ­{|b:z¢.z fbC€s–8œb:cbCzz‡ cRlOŠ—ŠN›Wz ,b:lOŠ—€ƒbC{|R€‚ÂSi a8œ¢ecOŠl{ ‚*lOfly‚Q‚Rz ¢O€lLb:cO|›z Cb:lŠ—€ƒb,{WlRcˆfzybb{8d €¢OlOŠŠ—{|Rc.d z ,b:c!±–{¢!z ez ,bR‚ßlf}‚’z bCecˆzdybC€—›hœ› d cR€—zN|¡Cz9dRcd l’lAbC€—zf¡Cz 9v • ™Õ€‚VbCecORc¡CzRcšœ f¢OŠcOlAi ~WznTbzp– lOŠ—lOf¢cšbCec fc!cO§¡Cz0bCez8:zœ ‰epdRcd lRl¦bC€—zfz¡Bd lLb€—cOfbR‚P¡Cz9Š—€—¡cO°Š®z f1‰hbCec’ld {xn€ƒb:ehbCec©e€­‰ e|R€‚:Âz¡ cOlobCeWl ›Wz f1‰€—f€s‡ €yœlOŠ‚0nlO€ƒb:€—f‰|bCz ‚b:lb bCecRl.d {pRc¼yœ € Rcy‚0œ ‰ c.fybVRcy‚’cOlR¢eWlobb:cfybC€Œz fi ŸšŠŒcyl.DŠs{<¡CŠc¾ €s–€Š€Žb,{€—f|bCecšbC€—›<€­f‰<€‚9fccOcOly‚*›lOf8{<d lobC€—cOfbR‚0n€ƒbCel!‡ l f¢OcO €›<›|œ fzNc¡C€¢O€cOf ¢{f cOc!pbCecRld{xœ ‰ cfyb:Šs{Si Ç. . .  ËÙRÄÅOÇ : Ä Å ´  ÄNÅLÙ —Ù,â. fhbCecˆ¢OzezbR‚*‚,œ››l.D€‚’cO§€—f™*l– Šc & q Š—z8n@– ly‚RcOŠ€—f cxŸPg|Þ<¢OcOŠ—Š ¢Oz8œ fybSnl‚*lh‚,bC:z f1‰€‚ ¡:lO¢ob:z0¡Cz*cOlŠs{›z,b:lOŠ—€ƒbC{€—flOŠ—Š & ¹§z¡ bCec©Î Ò¢Ozez8bR‚0np€ƒbCel‡ lO€Šl– Šcˆlob:l8i1™ech‚,œ››l.’{ el.Ì8l.R|RlAbC€Œz§¡CzBbCecˆl‚¦‚Rz ¢O€lobC€—zfW– cobnWcOcfŸPgpÞ¢!zœ f8b 9 Ï1Ò¢OcŠ—Š‚  1k  ‡ c¦‚Cœ0‚ŸmgpÞ 9Ï1Ò ¢OcOŠ—Š‚  8k 0 nWly‚9ÎSisÏ  ¸NÏ

(25) Ÿ:q & iŽ¸° Ó i Î 9 €—f‚,bœ8€cy‚Vn€ƒbCe<ldd:z d€Œlob:cˆlob:l  & Òq && q8Î & qÎÞq Î Ï1q Ó Ò8q Ó0&  ivT‰RlOcOly‚Q‚Rz ¢€—lob:€—zfhn€ƒbCeŸPgpÞ<¢OcOŠŠ¢Ozœ fbSnly‚ßRcdzb:cO|€­f<‚Rz›ch‚Cbœ8€—c8‚ . Ñ q & ÎqÎÎ  ¤V€s‰8œ Rc©Î l 0 –1œbB– ly‚RcOŠ€­f cš‡ €—RlOŠ ŠŒzNlOhnWly‚9fzbS¡Cz8œ fhbzW– cˆl.f§€—fcd cOfc fbV€‚Â. ¡:lO¢ob:z0€—flOf8{z ¡ÚbCech‚,bœ8€—c8‚Ai. ·.

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(27)      !#"%$ a {›d8b:z ›lLbC€¢ˆ€‚QcOl‚Rc , ˜^~WÍ ‚Cb:l‰ cy‚ Ó lf|Þ 0nly‚ly‚¦‚’zN¢O€—lob:c!pnW€ƒbCe›z Cb:lŠ—€ƒb,{W€­f ‚Rz›<c Ñ q ·q & ÎqÎ & q Ó Î  8– œbÚfzybßlŠ—Š  & & qÎ Ó ‚bœ8€Œc‚ ¤V€­‰8œ ’c©Î8– Rqd zڂQ‚€s– Š­{WRcO¡,Šc¢obC€—f8‰ €­¡C¡:cRcOf¢cy‚*€—fhbCecˆl!¢O¢oœ RlO¢{<z¡V¢OŠ€—fN€¢OlOŠS‚,b:l‰ €—f8‰<z0ez›z‰ cfcO€ƒbC{<z¡V¢Oz ez bR‚0np€ƒbCe|Rc‚d cO¢ob HAL author manuscript. bCzˆbCe€‚V‡ lR€l– Šc1i ˜£~Í ‚,b:l‰ c©Þ<€‚Rc!l‚’cOqez8nco‡c.Rqnpl‚P¡Cz8œ fhbzW– cˆlh‚bC:z f1‰dRcO8€—¢ob:zVz ¡. inserm-00266588, version 1. cOlobCeD‚,œ››l.’{WelÌ1lR|Rl¦bC€—z q ÎSi ΠݸNÏ

(28) ŸRq & si Ï° Ó i#Î. ›z,b:lŠ—€ƒbC{<€­fWl ŠŠB‚Cbœ €Œcy‚9Rcd zbC€­f1‰<z fhbCe€‚ Ñ qÎ & q ÎÎq8ÎÞ q Ó Ò1q ÓÓ ° Ó ¹  Oi fˆbCe8Rc!ch‚,bœ8€—c8‚ ¢Oz›|d lR€—f‰d lobC€—cOfybR‚0nW€ƒbCe|˜^~WÍ ‚Cb:l‰ c©Þ<8€‚’cOly‚QcˆlobS– ly‚RcOŠ€—f cšn€ŽbCehbCez ‚Rcšn€ŽbCeh˜^~WÍ ‚,b:l.‰ cy‚ & ° Ó qy˜£~Í ‚,b:l‰ c©Þ|nWly‚*ly‚Q‚Rz ¢€lob:cOhnp€ƒbCe›z ’c bCelOflˆz8œ– Š—€—f‰€—fhbCec©elÌ1lRz¡.  & Ò8qÎÎq Ó Ò  i. kmz8n@– z y{›<ly‚L‚*€—fc¾  Ñ q ·1q8Î Ó q8ÎÞ q Ó Ï1q ÓÑ q Ó ·1q Ó ¸  l flOfl!c ›<€l Ñ qÚ·1q8Î Ó q ÓÑ q Ó ¸q Þ Ò  W n cRc©€—fcd cOfc fbŠs{<l‚L‚Rz ¢ €Œlob:cOhn|€ŽbCe§›Wz ,b:l.Š­€Žb,{<€—f‚Rz ›ch‚,bœ€—cy‚Aiyvxf lOcO›€lˆ›l{§– c ly‚Q‚Rz ¢ €Œlob:cOhn€ƒbCelš‡ lR€cob,{Wz¡0¢!z f €ƒb:€—zf ‚‚,œ¢Oel‚*c¾8bC:ld8œ Š—›z fl{W™ß»%q‰ ly‚,bC:z €—fb:cy‚,b:€—flOŠ «pld z ‚R€ ,‚‚Rl.R¢OzN›lˆl.f‚Qc‡ cRcˆ›lOŠ—f8œbCR€ƒbC€—zfz 9›Wl!{pQcO¡,ŠcO¢obbCecˆ€sRcO¢obßc¡C¡:cO¢obR‚*z¡ lOy‡ l f ¢!cOh~|žÁz fpelOcO›<lobCzdz€—c8‚R€‚LiO£lOŠch‚Rc¾|nWly‚*l8‚¦‚’zN¢O€—lLb:cOhn€ƒbCe|d zzRc*‚,œ ,‡ €s‡ lOŠ €—f Ñ ‚,bœ8€Œc‚  Ñ qÚ·1q & Ò1q ÎÎq ÎÞq Ó ¹  OÝ bCec©RcOl‚RzfN‚*¡Cz SbCe€‚*l’cšœ f8 fz8n|fq–1œb9¢.z8œ Š—|RcOŠlLb:c bCz €­¡C¡:cRcOf¢cy‚*€—fecOlOŠƒb:e‚Rc!cÂN€—f‰– cOel‡ €—z8œ *z VdzzRc b’cOlobC›cOfybßlO8ecRcOf¢!cˆl ›WzNf8‰<›cOf Þ &  i . f¢!z fbCRly‚b bCzl¦b:l©¡Rz› e€—‰ e°€—f¢OzN›Wch‚QcobbC€—f8‰S‚Î  8q €­f¢RcOl8‚R€—f‰<l‰ cšnWly‚*ly‚Q‚Rz ¢ €lob:c! n€ƒbCepe€­‰ ec.P›z,b:lŠ—€ƒbC{pD€‚:€—fzfŠ­{<zfcˆ¢Ozezb , ·  i™0ecˆŠl!¢Â<z ¡VlOfly‚Q‚Rz ¢ €lobC€Œz f›<l{ Rc¡CŠc¢ob bCec©{zœ f1‰ c*l‰ cˆlf§flRz8nc.9l‰ cˆ8€‚,bC:€Œ–1œb€zf|z¡Sd lob:€—cOfybR‚9Rc!¢OcO€Œ‡ €—f‰v • ™6€—f vx¡D€¢l8ivhŠŽb:cf lobC€s‡cOŠs{ q8bCe€‚*›l{j‚R€›dNŠ—{|RcO¡ŠcO¢Lb bCec©RcOŠ—lLb€s‡ cOŠ—{j‚Rez,bVyœ Rl¦bC€—zfz¡0¡CzNŠ—Š—z8n° œ d€—fhbCecy‚Qch‚Cbœ8€cy‚‚R€—f ¢Ocˆ€­›<›|œ fzNŠ—z‰N€—¢!l Š RcO¢!z‡ c{8œ R€­f1‰|bCec©¡C€­Q‚,bVÞ›z fbCeN‚*z¡ bCRcOl¦bC›cOfybV€‚9fzbVl.‰ cO°cd cfcOfyb  ÞÎ °,ÞÞ  i ¯ lobC€—cOfybR‚Vn€ƒbCe™0»TlLbVcf8’z Š—›<cOfyb bz§v • ™`d:z ‰1RlO››c8‚9el‡ cˆlˆe€s‰Ne›z,b:lŠ—€ƒbC{R€‚  Þ Ï1q Þ Ñ lfW{cobVd lRlO1z¾ €Œ¢ylOŠ—Š­{§™ß» lOf™ß» 8€‚RcOl8‚’cˆlO¢obC€s‡ €ƒbC{el‡c©fz8bS– cOc.f§¡Cz8œ fhbzW– c €—f cd cOfcOfybV€‚:¡ClO¢ob:z¦‚9¡Cz9›zb:l.Š­€Žb,{Wyœ R€­f‰<v • ™ . Ñ q Ó ÏqÞ ¹  i ?lf8{WNcOlLbCeN‚Rqez8nWco‡cRq. ¸.

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(30)      !#"%$ ›<l{<zN¢!¢oœ 0– cO¡CzRc©v • ™Õ€‚*€­f€Žb€lob:cO Þ ¹qÞ ·  .l flŠ‚Qz|›hœS¢Oez¡ bCecšb®,œcš–8œ Rc.fz ¡ €‚QcOly‚’c±›<l{|’c ›<lO€—f|œ fly‚Q¢Oc,b:l.€­f c!  Þ ¸  Oi f¢Ozfyb®Rly‚CbCq cAb:cO¢¦b:lo– Šcˆ¢{1d8b:zN¢.z ¢O¢OlŠ lOfyb:€s‰ cOf€—f ‚Rc.,œ ›@nWly‚*lOf€—f cd cOfcOfybVdRc!8€—¢ob:z0z¡VcOlRŠs{<›z Cb:lŠ€ƒbC{€—f<l©,œ RlOŠ ¢Ozezb´€—fh¥p‰ lfNl HAL author manuscript. ,Ï1Ò  i . vxŠƒbezœ ‰exbCecšb{1d cˆz ¡Vv • ™`Rc‰ €—›<c fWl fhbCecšb{1d cˆz ¡VecOlOŠƒb:e¢!lRcˆ¡ClO¢O€Š€Žb,{,dR€›<l{ ‡ c.¦‚,œV‚‚Rc!¢Oz fl{ 9el!‡ c±fzb– cOcOf¡Czœ fhbCzW– cˆly‚¦‚’zN¢.€lLb:cOhn€ƒbCe›zb:lOŠ—€ƒbC{ ,·1q & Î q8Î Ó °,Î Ï  q dRz‰8Rl.›§›<c8‚*€—fhne€¢Oe|d lobC€cOfybR‚0nWcRc©Rc!¼yœ €sRcOhbCz|d lo{W¡Cz *›cO€¢ylLbC€—z fxnc’cˆly‚L‚Rz ¢O€—lob:cO. inserm-00266588, version 1. n€ƒbCeWl©Þ °,¡CzNŠ—|‰RcOlLb:c9›zb:lŠ—€ƒbC{R€‚  & Î  i™9e€‚*¢!z f¢!œ Q‚0n€ƒbCehbCec©¡,€—f €—f‰ ‚*zN¡Vl±›Wcob:lO° lfl Š—{ ‚Q€‚*z ¡ bCRc!lobC›cOfybVz8œ8b:¢.z›c8‚P€—f|’cy‚Rz8œ R¢OcO°Cdzz‚Rc¦bbC€—f8‰ ‚LݏyœcšbCzŠ­€—›<€ƒb:lob:€—z f ‚*€­f ¡€—f lOf¢Oc8‚’q d lobC€Œc fbR‚0npez§elOhbCz|d lo{pd l,bVz9l.Š­ŠbCecˆ¢!zN‚,bVz¡ bCecRl.d {pe lOlfldd’z¾ €—›<lob:cOŠs{ Ó Ò. Š—z8nc.9dz8– lo– €Š€ƒbC{WzN¡Se l!‡ €—f‰<lfhœfcLb:cO¢ob:lo– Š—c©‡ €—RlOŠNŠŒzNlOlob Ñ lf & ΛzfybCe ‚. ¢Oz›|d lRc!pbz§d l¦bC€—cOfybR‚0npez ‚Rcˆ›cO€¢lobC€—zfhnl8‚‚Cœ ddNŠ—€®cO|¡RcOcˆz¡0¢Oel‰ c &.Ó if| c!cd€—f8‰ n€ƒbCexbCe€‚’q v • ™IlO8ec’c f¢c©el8‚0– ccOf¡Czœ fhbCzW– c©dRc. €—¢Lb€s‡ cˆz¡0›Wz ,b:l.Š­€Žb,{  Ó ¸qÞ &  i • €‚:¡ClO¢ob:z¦‚9¡Cz0›Wz ,b:l.Š­€Žb,{›<l{<lOŠƒb:c*yœ R€—f8‰|bCecˆ¢Ozœ¦‚Rc©v • ™Hi ˜ e€Šc±›Wz ,b:l.Š­€Žb,{ yœ R€—f8‰|bCec©¡C€—¦‚,bVÞ›zfybCeN‚z ¡Vv • ™Õ€—fzfcˆ¢!z ez bSnlO‚*ly‚Q‚Rz ¢ €Œlob:cOhn€ƒbCe|d lLbC€—cOfyb ¢elRlO¢ob:c.D€‚,b:€—¢8‚*lobS– ly‚’cOŠ€—f cOqN›zb:lŠ—€ƒb,{– c!{zNfhbCe€‚0b:€­›<cO°Cd zN€—fybSnl‚9zfŠs{<ly‚L‚Rz ¢O€—lob:cOhn€ŽbCe bCecšœ d lLb:cO|lo–‚RzNŠƒœb:cˆŸPgpÞ<¢OcOŠ­Š ¢!zœ fb9lLbSÞ›z fbCeN‚*lOfpnW€ƒbCe¡lO€—Šsœ Rcˆz ¡S‡ €sQlOŠNŠ—z lO ‚,œ dd’cy‚¦‚R€—z f ÎÎ  i™9ecy‚’cˆlob:lh‚,œ ‰‰ c‚,b bCelobNbCec©Â c{Šzf8‰ °b:cL› cob:c.D›€—f lOfybVz¡0›Wz ,b:l.Š­€Žb,{ €‚0bCec©’cy‚d zfN‚’cšb:zWv • ™Ily‚*lOŠ‚Rzj‚,œ ‰‰ cy‚Cb:cOh–{›zRc©RcO¢!c fbV¡,€—f€—f‰B‚*¡Rz› v±– €L²¦lOf  Ó ·  i à  ØBÇQÆOÇÄßÊBÆ 8 Ù  ¤V€s‡cˆz–‚Rc‡ lLb€—zflOŠ ¢Ozez,b9‚Cbœ8€—cy‚*¡RzN› l©’lf8‰ cˆz¡V¢yz8œ fybC:€—cy‚*€—f‚,œ – °¦a lOel.RlOf§vx¡R€¢Ol Rcd z8bVzf±bCech‚d cO¢LbC,œ › z ¡V¢OlLœ0‚’cy‚*z¡0c!lRŠ­{WNcOlLbCeN‚Î & qÎ Ó q Ó Ïq Ó ¸8q Ï &  i™ec±›z ‚,b €›d zb:l.fybߢOloœS‚’cy‚*z¡0c!lobCe|Rcd z8b:cO|€—f¢OŠsœcšbœ– c’¢oœ Š—z ‚R€‚’qNl!¢oœb:ch‚Rcd ‚R€‚’qN¢{1d8b:z ¢z ¢O¢OlŠ. &Ò.

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(32)      !#"%$ ›<cOf€­f‰ €ƒb:€‚RqN›lOŠ€­‰ flOf¢ €c8‚  c‚d cO¢O€lOŠŠ­{p«ld z ‚R€ ‚m‚RlR¢z›l * lf¢ e1Rzf€¢ˆ€—l:DezNc!lˆz8 nWly‚,b:€—f8‰j‚{f8RzN›c8i g€—l.‰NfzڂCbC€¢ˆ¡ClO¢O€Š€ƒb:€c‚*lRcˆŠ—€›€Žb:cO§€—f›<l f8{}‚RcobbC€—f8‰ ‚’qNc‚d cO¢O€lOŠŠ­{W¡Cz 9,œ ’lŠ ¢Ozez,bR‚Rqlf HAL author manuscript. fz€— c fbC€—¡€l!– Šcˆ¢OlLœS‚Qcˆ¢Ozœ ŠŒW– cˆ€—cOfyb:€—¡€cO§€—fl©d’z dz8,bC€—zfz ¡VcOlLbCeN‚Li.³<z}‚{ ‚Cb:c ›Wlob€Œ¢©d zڂCb:° ›z,b:c› ‚Cbœ €—c8‚*z¡VcOlobCe ‚*yœ R€­f1‰v • ™`el‡cš– cOcOf|RcOd zb:c!|lfhbCec©z8‡ cRlOŠ—Šlob:lˆlRc bCec.RcO¡Cz Rc©Š—€›§€ŽbRcO iOgWcOlobCeN‚*€—fhbCec©¡,€—¦‚CbBnWcOc ‚z ¡Sv • ™IlRc©Š—€— cOŠ­{xb:zW– cˆ¢!loœS‚RcOh–{ ¢Ozf€ƒb:€—z f ‚0bCelLb9l.Rcˆc€ƒbCec9dRcO°cL¾ €‚Cb€—f1‰lLb0d:z‰8Rl››}cˆcf8RzŠ—›<c fbßz Vfcon ¢Oz f €Žb€—zfN‚. inserm-00266588, version 1. lR€‚R€—f‰€—fhbCecˆ¢Ozfyb:co¾1bVz ¡Sd cQ‚R€‚Cb€—f1‰€—››|œfz c ¡C€¢O€cOf ¢{iy:fz fch‚,bœy{W¢OloœV‚Rcy‚z ¡VcOlobCe yœ R€—f8‰|bCec©¡C€—¦‚,bVÞ›zfybCeN‚z ¡Vv • ™ànc.Rc±¡Cz8œ fhbzW’c¡,ŠcO¢LbBbCezڂ’c©z ¢O¢oœ C€—f8‰w²’œS‚CbVd€—zBbCz v • ™ n€ŽbCehbCecˆlO€ƒb:€—zfz ¡VcOlLbCe ‚*yœcšbCz|€—››|œfc©RcO¢!z f ‚,bC€ƒbœbC€—zf€‚RcOl8‚Rcˆl‚L‚Rz ¢ €Œlob:cOhn|€ŽbCe ¢{1d8b:zN¢.z ¢O¢OlŠ ›<c f€—f‰ €ƒb:€‚l fhbœ– cR¢Lœ Š—z ‚R€‚Î &  i ™0»^nWly‚*lO›zf8‰|bCecšbnpz|Š—clO€—f8‰<¢OloœV‚Rc‚*zN¡VcOlobCe€—f|Þz¡ bCechÏp¢OzezbR‚:q lO¢O¢.zœ fbC€­f1‰ ¡Cz0œ dhbCzÎ &. z¡VcOlobCe ‚Î & qÎ Ó q Ó ¸8q Ï &  i~pz8ncL‡ cRq ™0»X€‚*Š—€— cOŠ—{hb:zh– cˆl.fhœ fcR°. Rcd z8b:cO¢OloœS‚’cˆz ¡VcOlLbCe i ¯ zڂb:°,›Wz b:c› ‚,bœ€—c8‚9el!‡ c±¡Cz8œf§€—fhbCec©dRcO°,v • ™IcRl bCelobSœ dhbCz ÏÞ z¡ œ fybCRc!lob:cO|d lAbC€Œc fbR‚*8{€—f‰¡Rz› vˆ,gja<€­fpvh¡CR€¢!l±el!‡ cˆc‡ €cOf¢Ocˆz ¡Vz ¢O¢oœŠƒb €‚L‚RcO›€—f lob:c!§™0» , ÏÎq Ï Ó  lf±bCelLb bCe€‚*›<l!{p– cˆlˆ¢Oz››z fhœ fcRŠ—{ €­f‰<¢OlLœS‚RcˆzN¡ ‚RŠ€› €‚QcOly‚’c  ,ÏÞ  i vhŠŽbCez8œ ‰ehnl‚,b:€­f1‰j‚{f 8Rz›c  cO¡C€­f cly‚0nWly‚CbC€­f1‰|n€ƒb:ehœ fc¾d ŠlO€­f c!§¡:c!‡ c lf B z ߢe8Rzf€—¢ˆ€lezNcOl 0nly‚m‚d cO¢O€—¡€¢OlOŠŠ—{Rcd zb:c.ly‚*lf€—›d z Cb:lfybV¢!loœS‚Rcˆz¡VcOlobCe lO›zf8‰€—fzfŠ­{Wzf cˆ¢Oz ez b  Î &  q bCe€‚*›l{<el‡ c©– c!c f›zRcˆ¢Oz››zNfl‚ ¢Oe1Rz f€¢ €—lezNc!l  nWl8‚*lOŠ‚’z§Rc.dzb:cOply‚*lˆ¢.z ››zNfW¢OloœS‚Qc Ó Ï  l fhnly‚CbC€—f8‰|nl8‚*lˆ¢!z ››zNfpD€‚ ¡:lO¢ob:z0¡Cz9›z b:lŠ—€ƒbC{<€­f›<lOf8{<¢OzezbR‚ly‚*cy‚’¢R€Œ– cOclRŠ­€cAi ™9ecˆ¢OzfybC€s–1œb€—zfz¡V™ß»T€—››|œ fc©RcO¢OzfN‚Cb€ŽbœbC€—z fW €‚Rcly‚’cšbCz›z b:lŠ—€ƒbC{e ly‚9{ cLb bCz¡œ Š—Š­{ cO›c‰ cCÏÏ  i ˜¿e€Šcˆ›z ‚,bߢOly‚’cy‚*ldd cOl.0bCzh– ch‚’c Š—¡:°Š€›<€ƒb:€­f‰ q ‚Rz›cˆl’ch‚Rc‡ c’cˆlfcOlobCe ‚ el‡ c%– cOcOf|Rcd zb:c!W¡’z › ¢OzezbR‚9€—fja zœ1bCe|vh¡R€¢OlˆlOf™9elO€ŠlOf ,Ï Ñ q Ï1¹  i ~pz8ncL‡ cRq – l!¢Â‰Rz8œ f§›Wz ,b:l.Š­€Žb,{pRlob:cy‚Vnc’cˆl Š‚RzW‡ c{e€—‰NeWl ›}z f1‰<™ß»¿d lAbC€Œc fbR‚0npez8€Œ§fz8b. &&.

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(34)      !#"%$ co‡ c ŠŒz d|bCe€‚*¢OzN›pdNŠ—€¢lobC€—zflOf§fcO€ƒbec‚,bœy{W¡Czœ f§€›<›|œ fc©RcO¢OzfN‚Cb€ƒbœ1bC€—zf €‚’cOl8‚RcšbCz – cˆl‚L‚Rz ¢ €Œlob:cOhn€ƒbCelh‚R€ ‰Nf€¡,€¢lOfybßco¾ ¢!cy‚L‚*›z Cb:lŠ—€ƒb,{pR€‚ÂSiOkml‰ c9d:zڂ:d cO¢obC€ƒ‡ch‚Cbœ8€—c8‚*lRc fc!cONc!pbz¢ ŠŒlR€­¡C{hbCe€‚*€‚L‚,œc8i HAL author manuscript. Ÿ{8d8b:z ¢.zN¢O¢!l Š ›cOf€—f‰N€Žb€‚0nWly‚*lO›zNf1‰|bCecšbnpz|ŠcOlO€f8‰<¢OlLœS‚Qcy‚*z¡0›z,b:lŠ—€ƒbC{€—fÞz¡ bCechÏp¢.z ez bR‚  Î & q8Î Ó q Ó ¸qNÏ &  q lO¢O¢!zœ fObC€—f8‰<¡Cz 0œ dhbzhÎ Ò. z¡VcOlobCe ‚LiO£lOf8{z ¡ÚbCecˆcOlobCe ‚. ¡RzN› ¢.’{d8bCz ¢Oz ¢O¢OlŠ €‚RcOl8‚Rcˆ€—fl|a zœ1bCe|vx¡D€¢OlOf¢!z ez ,bnc’cˆlAbb€s–8œb:c!pbz|€­›<›|œ fc RcO¢!z f ‚,bC€ƒbœbC€—zf€‚RcOl8‚RcCÏ·  l fhbCe€‚0nWly‚*lˆ›zRcˆ¢Oz8›<›zNf¢OlLœS‚Rcˆz¡0c!lobCehbCelOf™0». inserm-00266588, version 1. €›<›|œ fc©RcO¢OzfN‚Cb€ƒbœ1bC€—zf €‚’cOl8‚RcÎ &  iO£l.f8{|d lob:€—cOfybR‚mco‡ cOŠ—z d €—f‰|bCe€‚*¢OzN›pdNŠ€¢!lob€Œz f|e l‡ c dRco‡ €ŒzœS‚RŠ—{§– cOcOfhbCRcOl¦b:cO|¡Cz*¢,{1d8bCz ¢Oz ¢O¢OlŠ ›<c f€—f‰ €ƒb:€‚Vn€ƒbCe¡,Šsœ¢Ozfl.ÌzNŠ—cˆ›zNfzbCecRld{ Î & q Ï·q Ï1¸  Oi vxŠƒbCezœ ‰ehbCe€‚*€‚0bCech‚Cb:lfl.Rz ¡V¢Ol’c be1Rz8œ ‰ez8œbS›hœ¢Oez¡0vx¡D€¢Ol!q . ¡Šsœ¢OzflÌ zNŠ—cˆ€‚l±¡œf8‰ €‚,b:lobC€—¢ˆ8Cœ ‰WnW€ƒbCe¡ClPŠŒc‚Q‚*cO¡,¡:€¢lO¢{xbCelOflO›dNezyb:c€—¢O€—f€—f¢OŠclR€—f8‰ bCecˆz8:‰ lf€‚R› ¡Rz › ¢OcRc–’zڂ:dN€—flOŠ ¡CŠsœ €  Ÿˆa8¤ * lf§c8‚:d cO¢O€lOŠŠ­{j‚’z§€—fhbCecˆ¢!z fb:co¾8bVz¡ ¡Šsœ¢OzflÌ zNŠ—c©Rcy‚R€‚Cb:lf ¢Oc Ñ Ò  i ¯ cQ‚R€‚,b:cf¢OcˆzN¡V¢{1d8b:zN¢.z ¢O¢€ z*¢,{1d8b:zN¢.z ¢O¢OlŠ lOfyb:€s‰ cOf€—fhbCec Ÿˆa8¤à€‚*Š—€­Â cOŠ—{|b:z|dRcO8€‚:d zڂ’c©d lobC€—cOfybR‚0bz§€—››|œ f c©Rc!¢Oz f ‚,bC€ƒbœbC€Œz f€‚RcOl8‚’cOqnpe€¢Oe|e ly‚*l e€—‰Ne›z,b:lŠ—€ƒbC{pD€‚: C Ï·1qÚÏ1¸q Ñ0& q Ñ Î  i «pld z ‚R€ ,‚‚Rl.R¢OzN›lˆl.fzbCec9›lOŠ€—‰ flOf¢O€c8‚0nWcRcˆlO›<z f1‰hbCecšbCe1RcOc©ŠcOlO€—f‰¢!loœS‚Rc8‚*z¡ cOlobCe€—f Ó z¡ÚbCechÏp¢zezbR‚  Î & q Ó Ï1qNÏ &  qNl!¢O¢z8œ fybC€—f1‰¡Cz0œ dhbCz & Þ z ¡VcOlLbCeN‚Livx¢oœb:c ‚Rc.d ‚R€‚Vnl8‚*lfzbCec9€—›d z ,b:l.fybV¢OlLœS‚Rcˆz¡0›z,b:lŠ—€ƒbC{€Nc.fyb:€­¡:€c!§€—f‚Rz ›cˆ¢OzezbR‚*c‚d €ƒb:c n€—c8‚:dRcOlOhœS‚Rcˆz¡ bC€—›<cobCezd€—›<°D‚,œŠ—dNel ›<cobCez¾l.ÌzNŠc  ¢Oz°bC€—›z8¾lÌzNŠ—c Rq  Î & q Ó ¸  i • cy‚d €—Rlob:z8,{W€‚’cOl8‚RcOq lO¢oœb:c©‰ l‚,b:z cfyb:c:€ƒb€‚*z ‚C{ ‚Cb:c ›€¢h‚Rc.dB‚R€‚0n€ŽbCe§fz§€—cOfb€—¡€l– Šc±¡Cz ¢oœS‚ nWcRcšbCec©›WzڂCb9¢.z›§›WzNf¡Cz R›‚*z¡9‚RcdS‚R€‚*lOf¢OzŠ—Šc¢ob®€s‡c Š—{j‚Rc.dB‚R€‚*lO¢!¢Ozœ fb:cO|¡Cz 0œ dxbCz &¸. z¡VcOlobCe ‚Li  

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(44)   8  ­  iyvxŠƒbCez8œ ‰ee€—‰Ne|’lob:cy‚ßz ¡. ¢Oz °®b®€—›z ¾ l Ì z Šc©Rcy‚R€‚Cb:lf¢OcˆlO›z f8‰fzf°bC{1dNezN€—lOŠS‚RlOŠ›z fcOŠŠlOcˆlOf|df coœ›z ¢Oz ¢O¢OlOŠ HAL author manuscript. €‚RzNŠŒlob:cy‚9e l‡ cš–c!c fpRcd zb:cOx€­fx¥|‰ lOflˆlOfp?lOŠlLn€  Ñ Ñ q Ñ ¹  q d1zde8{Šl¾ €‚0n€ƒb:ehbCe€‚ 8,œ ‰€‚‚Cb€—ŠŠ cO¡C¡cO¢Lb€s‡ cˆ€—f|RcOyœ¢O€—f‰›Wz ,b:l.Š­€Žb,{€—f– z8bCe|¢Oz8œ fybC:€—cy‚ Ñ ¹q Ñ ·  i ™9ecˆ›zڂCbSn|€—cOŠ—{|œS‚RcO|Rc.‰N€—›<cOf ‚P€—fvx¡D€¢Olˆ€—f ¢OŠŒœch‚b:lL‡8œ€­fc  8Þ ™ * lf|fc‡ €sQld €—f cOq npe€¢Oeel‡ cšbCec©d zyb:cfbC€—lOŠ ¡Cz ‚’cR€—z8œS‚Bbz¾ €—¢O€ƒbC{<€—f ¢ Šsœ€—f‰§e c.d lob:zybCz8¾€¢O€ƒbC{qSa8b:co‡ c.f ‚R°. inserm-00266588, version 1. ze8f ‚’z f<‚{f 8Rz›<cˆlfŠl!¢ob€Œ¢ˆlO¢O€z ‚R€‚ Ñ ¸q ¹Ò  i~pzynWco‡ cRq 8,œ ‰hbCz8¾ €—¢O€ƒbC{z cy‚*fz8b . ldd cOl.0bCzh– cˆl©›<l²Rz*¢OloœS‚Rcˆz¡VcOlRŠs{<›z Cb:lŠ—€ƒb,{i8vx›zNf1‰ÎÎ Ñ c!lobCeN‚9’cd z b:cO±–{pÞ ¢OzezbR‚’q¹  Ó i &. 0nc’c©l¦bbC€s–8œb:c!±bCzv • ™×bz¾ €—¢O€ƒbC{  & ÒqÎ & qÎ Ó q Ï &  i™ecy‚RcšnWcRc. ¢Oz›|d lRlLb€s‡ cOŠ—{|ncOŠŠ—°,Rcy‚’zœ ’¢OcO|dRz‰8Rl››<c8‚0n€ƒbCeWlO¢¢Ocy‚¦‚Vb:zp– €ŒzN¢ecO›€¢l Š Šl– zRlobCz8C{ ›zNf€Žb:z €—f1‰BÝ›Wz ,b:l.Š­€Žb,{pRlob:cy‚*›l{– c©e€—‰ e c0npecRcˆ›<z f€Žb:z8€—f8‰€‚*fz8bSdzڂQ‚R€Œ– Šc8ivxflOŠ­{‚R€‚ z¡ÚbCecšb:c›|d zRlŠ €‚,bCR€s–8œbC€—zfzN¡V8,œ ‰j‚,œ–‚,b:€ƒbœbC€—zfN‚*yœcšbz±bCz8¾ €—¢O€ƒbC{j‚Rez8n<‚0bCelobÚfco‡ €—Rld €—f c lfWÌ€z8‡8œ€­f c C v m ™ B bz¾ €—¢O€ƒbC{<z ¢O¢oœ *yœ €—f1‰WbCec©¡,€—L‚,bV¡Ccon ›Wz fbCeN‚*zN¡Sv • ™ npecRc!ly‚ ‚,b:lL‡8œ€­f c : 8Þ ™ R°:ly‚¦‚’zN¢€Œlob:cO±bz¾ €—¢O€ƒbC{j‚Cœ¢ eWl‚*Š—l!¢ob€Œ¢ˆly¢O€—z ‚R€‚*z ¢O¢oœ ¦‚*¢Lœ ›hœ Šlob:€s‡ cOŠ­{<¡Rz › lRz8œ f Ñ ›zfybCe ‚*z fnl.RN‚¹ & q ¹8Î  i ™9eyœS‚’qbCecˆ¢zfybCC€s–œb€Œz fz¡V8,œ ‰hbz¾ €—¢O€ƒbC{|b:z|z8‡ c.RlOŠ­Š ›z,b:lŠ—€ƒbC{<›l{<¢Oel f1‰ cˆz‡ c0bC€—›<cˆlf›l{pdRzd z bC€—z8flLb:c Šs{<€—f ¢RcOl‚Rcˆl8‚0bCec©:€‚:Â<z ¡ zddzbœ f1€‚Cb€Œ¢±€—f¡:cO¢ob:€—z f ‚*€›€—f €‚Rec8‚*lO¡b:cBbCec©¡,€—¦‚Cb Ñ ›zNfbCeN‚*z¡0v • ™Hi gWcOlobCeN‚ly‚¦‚’zN¢O€lob:cOhnp€ƒbCefc‡ €sQld €­f c!°’€—fyœ¢yc!Wecd lob:zybz¾ €—¢O€ƒbC{e l‡ cš– cc fpRcd zb:cO ¡RzN› a z8œ8bCe|vx¡R€¢ylšnpecOfhœS‚’cO¢Ozf¢oœ ’c fbŠs{xn€ƒb:e|R€—¡RlO›|dN€¢O€—f  Ñ ¸  8– œbV›zRcˆl¦b:l©¡Rz › Šl‰ cˆ¢OzezbR‚*lRc©fcOcOcOhbCz¼yœlfbC€—¡,{hbCec©R€‚:Â<z ¡V¢Ozf ¢oœ Rc.fybߙ߻IbCRcOl¦bC›cOfybQif¢OzfObCRly‚CbCq cO¡Cl‡ €­’c f1Ìh€‚0‡ c{|nWc ŠŠ8b:z ŠŒcRlob:cO  Ñ Þ  l f¢Ozf¢Lœ Rcf8b œS‚’cˆz ¡S€—¡:lO›§d €¢O€­f<lOfcO¡Cl‡ €—RcOf8Ìx€­f ¢OzezbR‚߀­f}aNz8œ8bCepvh¡R€¢Olˆ€—§fzbS’cy‚,œ Šƒb߀—f§›Wz ,b:l.Š­€Žb,{  Þ ¹qN¹ Ó i. &.Ó.

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(46)      !#"%$ ÙRÅ8ÙRÆÆ!ÇPÙRÄÅÆ!ÊBØSËOÆ ´  Ä ÅoÙ ­Ù,â µ lŠs{<›z Cb:lŠ—€ƒb,{WRlob:cy‚*l.Rch‚bCzf8‰ Šs{l8‚¦‚’zN¢O€lob:cOhnp€ƒbCehb®ecˆc‰Rc!cˆz ¡V€­›<›|œ fzNcO¡C€¢O€cOf¢{<€—f d lobC€—cOfbR‚*lob bCec bC€—›<cšbCec{cOf1RzNŠ €­fb:z§v • ™`d:z‰8Rl››}cy‚Li aybCRl¦b:c‰€—c8‚0bzW’cOyœ¢Oc©›z,b:lŠ—€ƒbC{ HAL author manuscript. ›|œS‚,bSbCec.Rc¡CzRc©¡CzN¢LœS‚9fz8bVzfŠŒ{WzfcOŠ€s‡c{z ¡0¢!lRcšn€ƒbCe€—fv • ™6dz‰Rl››<c8‚0–8œbV›zRc. inserm-00266588, version 1. NÅ sâ  Ê   ÉSÄÇ Ç ÉSÊ  ÄÉ ­ÙRØSÊ  É   Ë Å.Æ    Æ

(47) RÛ ¯ l¦bC€—cOfybR‚*cfb:cR€—f8‰v • ™. ¡œ fl ›<cOfyb:lOŠ—Š­{xbCec{<›|œS‚,bVd:z ›z8b:cˆcOl:ŠŒ{x~pž €—l‰ f zڂ:€‚*lf€›dRz8‡ cO|dRc!°,v • ™ ~pž ¢Ol’c  ™PlL– Š—c©Î Li. dRz‰8Rl.›§›<c8‚*€—f‚,œ – °¦a lOel.RlOf|vh¡CR€¢Ol±el‡ cšb{1dN€¢lOŠ—Š­{<elOhbCec € 0~|ž €—f¡:cO¢ob:€—zf €Œl‰Nfzڂ’cO ¡CzNŠ—Š—z nW€­f1‰dRcy‚RcOfb:lobC€—zfhb:z±bCec©ecOlOŠƒb:e‚Rc‡ €¢Ocy‚Vn€ƒb:elOy‡ lOf¢yc!}‚{›d8b:z ›lLb€—¢ˆ€‚Rcly‚’c8i a8œ¢e|d lobC€cOfybR‚ßel‡ c©e€—‰ e§›Wz ,b:l.Š­€Žb,{pR€‚:€—fhbCec©d cR€—z |ŠcOlO€­f‰|œ d|bCz|v • ™Õl‚0ncOŠ—Š l8‚ yœ R€—f8‰<cOlRŠs{v • ™  ¤V€s‰8œ Rc©Î Li ¯ :z‡ €‚R€—zfzN¡VlO¢O¢!cy‚L‚R€­– ŠcˆlOfhœS‚Rc.R°¡D€cOfŠs{j‚Qc,‡ €¢Oc8‚*¡Cz ‚Rc.D€Œl Š ‡ zNŠƒœfyb:l.,{¢!zœ f ‚Qc Š—Š€­f‰<lOfhb:cy‚CbC€—f8‰ , žpŸš™ * lf§ŸPgpÞ<¢OcOŠ­Š ¢!zœ fb9c‚,bC€—›<lob€Œz f€‚0‡ €ƒb:lOŠ bCz|d:z ›Wzb:cwcOlŠs{|~pž €—l‰ fz ‚R€‚*lOfly‚Q‚Qcy‚¦‚R›<cOfybßz¡Bv • ™Ic Š—€—‰ €Œ–€Š€ƒbC{ iOµ lRŠŒ{§ €l‰ fz ‚R€‚ lf§€—f€ƒb:€lLb€—zfz¡VlddRzd€—lob:cˆŠ—zf8‰ €ƒbœ €—f lOŠ ¢Ol’cšnz8œ Š|d:z– lo– Š­{– cˆl‚¦‚Rz ¢O€lob:cOhn|€ŽbCe ›|œ¢Oe§ŠŒznWc*›z b:lŠ—€ƒbC{R€‚€—fhbCec©d cR€—z WŠŒcyl! €—f8‰|œ d|bCz|v • ™Õl‚0ncOŠ—Šly‚*yœ R€—f8‰|bCecˆ€—f€ƒb€lOŠ ›zNfbCeN‚*z¡0v • ™  ¤V€­‰8œ ’c©Î Li aN€—›€Šl0b:zˆbCecˆ›lOfl‰ cO›<cOfybßz ¡V›lOf8{¢Oe1Rz f€¢ˆ€‚RcOl8‚Qcy‚*€—fvh¡R€¢OlOqNŠŒz f1‰N€ƒbœ€—f lOŠ ¢yl.Rc ¡RzN›@bCecšbC€—›cˆz¡ ~|:ž €—l‰ fz ‚R€‚Vœ fyb:€­Š RcO¼yœ€sRcO›<cOfybV¡:z Vv • ™Õ€‚*z ¡b:c.f|d zNz8Ai™eœS‚Rq co‡ cOf bCez ‚Rc©d l¦bC€—cOfybR‚Vn|ezlRcˆ8€Œl‰Nfzڂ’cOhn€ƒbCe|’c ŠlobC€s‡cOŠs{<cOlORŠs{h~pž €—f¡c!¢ob€Œz fl.Rcˆz ¡b:c.f§ŠŒzڂCb bCz ›<cO€¢!l Š¢Ol’cˆz fŠs{|b:z|Š—lob:c.9RcO°cfb:c0›WcO €¢lOŠB‚’c,‡ €¢cy‚9n|€ŽbCelO8‡ lOf¢cO€‚QcOly‚’c8i kmzf8‰ €ƒbœ €—fl Š¢Ol’c±›hœV‚,bS– ch‚,bCRcf1‰8bCecfcOlOf‚Rez8œ ŠŒ§€—f ¢OŠƒœNch‚’¢RcOcOf€—f‰¡Cz*lf bCRcOl¦bC›cOfybBz ¡Vzddzbœ f€‚Cb€Œ¢±€—f¡:cy¢LbC€—z f ‚’qN€—f€ƒb:€lLbC€—z fWzN¡V¢OzN°b:€­›Wz ¾ lÌ zNŠ—c©dRzde8{Šl¾ €‚Rq €‚Rzf€l Ì€—|dRc‡ c fb€s‡ cšbCecRl.d {, ¯ ™ R q8Rcd:zNyœ¢¦bC€s‡ c©e cOlOŠƒbCeW¢OlRcOq lf}‚’cR€l ŠŸPg|Þ<¢OcOŠ—Š¢Ozœ fb. &Þ.

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(49)      !#"%$ ly‚Q‚Rc8‚¦‚R›<cOfybSœ fybC€—ŠcOŠ€—‰N€s–€—Š€ƒbC{<¡Cz 9v • ™Õ€‚9’cOlO¢OecO i1™9e€‚Vn€ŠŠRcO¼yœ€sQch‚,bCRcf1‰8bCecf€—f‰<z¡Ú~pž ¢Ol’ch‚Rc,‡ €¢Oc8‚*l.f§›Wz RcšnW€—c8‚dRcOl!§lL‡l €—Šl– €Š€ƒb,{§z ¡ßŸmgpÞ<¢OcOŠ—Š ¢Oz8œ fybV›c!l‚Cœ RcO›<c fbQi ¯ Rco‡ c fb€Œz fqڂ’¢RcOcf€—f‰<lOf›lOf l‰ cO›cOfbVz ¡Vzddzbœf€‚,b:€—¢±€—f¡:c¢obC€—zf ‚*lRc©fcOcO cO HAL author manuscript. bCe8’zœ ‰ezœ1bNbCecš~|žÁ¢OlRc©d l¦bCeynWl{i8ŸHz °®b®€—›z ¾ lOÌzŠc©dRzde8{Šl¾ €‚m‚Rez8œ Š—h–cˆ€—f€ƒb€lob:c!. inserm-00266588, version 1. co¾ ¢ Šsœ€—f‰l!¢ob€s‡ cˆ™ß»T€—f|d lLbC€—cOfybR‚0n€ŽbCe§›WzNc’lob:c©z9l.y‡ lOf¢cO€—››|œ fzNcO¡C€¢ €cOf¢{i ¯ ™. lO¡b:c0~pžE8€—l‰ fz ‚R€‚l f¢Oz fbC€—fyœÚcOyœ D€—f1‰§v • ™  ¹8Þ  yl ‚SbCe€‚*€‚l‚Q‚Rz ¢O€—lob:cOhn€ƒbCe lO€ƒb:€—z flOŠ‰ lO€—f ‚*€­fŠ€­¡:cˆc¾d cO¢Lb:l f¢{  &.Ñ q ¹NÏ  Oi ¦‚’z f€Œl Ì€—|dRcL‡c fbC€s‡cšbCecRl.d {, ¯ ™ 0 €‚*lf œ fc.,œS‚RcO€—fyb:c‡ cOfb€—zf€—f§vx¡R€¢Ol¹ Ñ iO«pc{z8– ‚Cb:lO¢OŠc‚P€—f¢ ŠsœcšbCecˆ €—¡¡C€¢!œŠƒbC{z ¡ nWzœ Š—hbCecRcO¡Cz ’cš– cˆ›z ’cˆcOly‚R€—Š­{xœ0‚’cOlO›zNf8‰d lobC€Œc fbR‚0n€ƒbCeŠ—c8‚Q‚*lO8‡ lOf¢cO€‚QcOly‚’cˆl f { cLb9l!8ecRcOf¢Ocšb:z±bCRcOl¦bC›cOfybßl›Wz f1‰ ‚Cœ¢Oe|d lob:€—cOfybR‚*lf ˆbCecˆ€­f¡’l‚CbC,œ¢obœ Rc bz§c.¡,¡€¢O€cOfyb:ŠŒ{ cOŠ—€Œ‡c.*lf›zNf€ƒb:z0 ¯ ™àRc›Wl €—f<lˆ¢e lOŠ—Šc f‰ c1i Æ ÆÅAâ}Ä.       Æ

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