• Aucun résultat trouvé

Socioeconomic status moderates the association between carotid intima-media thickness and cognition in midlife: evidence from the Whitehall II study.

N/A
N/A
Info
Télécharger
Protected

Academic year: 2021

Partager "Socioeconomic status moderates the association between carotid intima-media thickness and cognition in midlife: evidence from the Whitehall II study."

Copied!
26
0
0

Chargement.... (Voir le texte intégral maintenant)

Texte intégral

(1)Socioeconomic status moderates the association between carotid intima-media thickness and cognition in midlife: evidence from the Whitehall II study. Archana Singh-Manoux, Annie Britton, Mika Kivimaki, Alice Guéguen, Julian Halcox, Michael Marmot. To cite this version: Archana Singh-Manoux, Annie Britton, Mika Kivimaki, Alice Guéguen, Julian Halcox, et al.. Socioeconomic status moderates the association between carotid intima-media thickness and cognition in midlife: evidence from the Whitehall II study.. Atherosclerosis, Elsevier, 2008, 197 (2), pp.541-8. �10.1016/j.atherosclerosis.2007.08.010�. �inserm-00226364�. HAL Id: inserm-00226364 https://www.hal.inserm.fr/inserm-00226364 Submitted on 30 Jan 2008. 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 Atherosclerosis 2008;197(2):541-8 2007;:epub ahead of print.   

(3)       ! "#

(4) %$& #'( 

(5) )*+ "#%,

(6) "# -. &  #/&

(7) +0

(8) )  1

(9) &"#

(10) %2

(11) 34#567 98 ;: 6 

(12) < 7 => ?@&#   55A+AB!C D E HAL author manuscript. FHG"I<JK LKHM&NOLPJQ#RSK LT U VWX J Y[Z6\ ]\ ^!_ F`LLNbadcGNeeTL&W<X JYf] RgN2hiKkj(NlNmnK hN6W<XoJ Y ] Fqp#NIarUtsuPUta<LW<XoJ Y Z v Up#NK LxwfKp6I<TyV W<RzY(W*Rz{q|}X~. inserm-00226364, version 1. RgN#I+JKa*pyRSKGm[T e€WuRY(Wu‚ {H|X ] _ |ƒT GGa„† TyLt‡NLPxK U e6JTG&ˆ‰K‡‡ G"a „+„ Z6Š#‹[MŒ{ƒRŽW<(‘i’Q€Š6‚&{fi“ wH‹[MiRŽW •” GUad‡Ux–fKp‡— ˜H„La “ ””™*š MKNL eQ2R›K<UGNI<aH|}a<‡a<VW<‚GKLtIa œ ap<žŸŸ( ¡9¢ ƒ”&šn ‘fŸ9‘qŸ£<‚K+VžŸŸ¤ ¡¢ B”&š) ‘HŸ‘x‘i“ Œ0m[KNp FHG>I<JK+LK ¥OM N¦LPJQ#RSK LT U V9§¨„†e€Q©m[K UGNIa ¥ NL„+a<Gm4¥«ªG. ]Y(a< KG#e€m%a;LeT ªŒ0 N6‡ a<m%NTpT P ¬fK<Lt‡­XU ®tp#NIkw(a<Kupbe6J fL N¦ltauG„+Ne¬(|dTppa<PaB¯0TyL‡iTyL W<Hj ^"|ƒa;Le6G>aƒ‡a`rsGT L e€TpT9PtNaWuw(° N,e6KpM e€akX™suGNLtayWFdXQ#wfX ~ –fK*„+I<UpK<G&X J ¬9„N#TpT P¬HfL&N¦eW<Y(a< K Gem%a;L eT ª |kK*G‡NTpT9P¬ ŠL„†e€Ne#Ue6aƒTª&|BJN#p6‡­wfa Kp¦e#JWfLN¦l a<G>„±N¦e#¬(|ƒTp#paPiak¯²T L‡iT LW*Hj. ³ T G"‡¤I<T UiLye´;eN¦e©p#a  K®„†e6GCK*I<e>µ š µ ;e€a<V e± Ÿ ” ‘ ”. j(a<¬i¶fT G"‡ „I*auGa ®G>TyltK„±I<UpK<G ‡N„a<K*„a*„+WyI*T PyL N¦e€Nbl aƒK<PNOLPtWyIK G>Tye©N‡¤NL eNm[KQ#m%a‡NKke,J&NIhLa„!„.

(13) ($    /1  &

(14) & |T m[m[TL[IK<G"Tye€N‡xK<Gea G©¬(NLeNm[Kdm%a‡NOKke€JN#I<hiLa „+„ Š#R œ ¢ N6„²Kƒm%aK„!UGadTªPaLa<GKp6N*a‡ . HAL author manuscript. K e#Ja GT„IpaGT„N„K<L‡HJK„®a a<L[„>JT¶Lxe€TH®adK*„„!TIN2K+e€a<‡x¶fNeJ[IT PL N¦eN,ltaƒªULI<e€N2TL™¥ ³ aa;VK m%NLake€¶fT Ua„†e6NTyL „< ‡T a„}„†TiIN2Tia<I*TyLTm%NI„†e6K<e,U&„0 ´MiŒƒM¢&m%T‡ a<GK+eake€JN„²K*„+„!TIN2K+eNT L(K+L‡¤N6„ ŠR œ m%T9G€a„†e6G>TLPtp,¬ . Ku„„TiIN2K+e€a<‡f¶fN,eJ „´ taINªN#IƒK„† taI;e©„T ª IT P LNe€N,ltadªULI<e€NTyL <&  ;Y(K;e€KK G>a`‡ GCK ¶HL[ªCGT m‰e€JakX JK„±a’¤ #µ¡i¡ ŸQ2µ¡¡ ” ¢T ª9e€Ja ³ JN,e€a;JKup2p ŠŠ „´e€U‡y¬( €‹ Ÿ9‘i“i ¢†¥ ŠL . inserm-00226364, version 1. IGTi„+„Q„†a*I;eNTyLKup K<LKp¬t„a„oe6JadK*„„!TIN2K+eNTL¤®a<e6¶Haa+LxŠR œ KL‡(„N,V(m[aK*„´UGa„0T ª&IT PL Nbe€NTyL  C„!JTG#ee€aGm l9aG®K*p m[am[T G¬WN2L‡ UtI;eNlaƒG>a K„±TyL N¦LPtW<l T I<K ® UpK<G¬tW„am¤K L eNIdK L‡H JTL&a+m%N#Idª€p2Ua<LtI;¬fKL‡xKƒm%aK„>UGa T ª Pp#T ®KupI<TPLN,e€N¦l a„CeK+eUt„¢&¶HK„}a;VKm%NLa ‡¤NL¤K<LKupb¬9„!ay„K ‡ >U„†e€a<‡xªT G G>a;l NT Ut„²JN„†e6TG#¬(T9ªIT G>TLK G¬ JtaK<Ge ‡N#„±a<K„±aWyJta<Kp¦e6Jx®a JK<lNT UG"„K+L‡¤Tye6Ja<G&lK*„+I+Up2KG&GN6„†hfm%auK*„UG"a<„0„†UtI;J¤Ku„²®pT T‡H Ga„±„†UG"aW I JTpa„†e6aGTp K L‡­®tT ‡ ¬fmnK*„+„0N,L‡a+V ¥ !5" œ JadTyl9a<GKp6p K„+„±TIN2K+eNT Lf®a+e¶Ha*a<LxŠ#R œ K<Lt‡qe6J adfm)a K„>UG"a„T ª IT PL&N¦eNbT L¤¶HK„G"a„†e6G>N6I;e€a<‡­e€T

(15). e€Ja`p2T ¶ M ŒƒM¤PGTU [ # ¡¥«¡µ¢>¥ ³ N,eJNLxe6JN„PGT U W*ŠR œ ¶HK„0„+NP LN2ª€N#I<K*L ep¦¬fK„„±T INK;e©a<‡f¶fN,e6J[N¦L‡UI;e€N,lta G"a<K„!TL&N¦LP( #  ¡¥ ¡ ¡ ¢WlTIK+®UpKG#¬  © ¡¥O¡i¡yµ¢Wu JtTyL a;m%N6I #  ¡¥O¡i¡ ¢&KLt‡¤„!aum[K+Le€N2IƒªpUauLtI;¬  # o¡¥ ¡yµ¢!¥ œ JaƒI TylK<G"NK<e€a„a;VK m[NLa ‡¤a;Vi &pKNOL&a ‡xK+®TyU e K . UKG#e©a<GT ªeJaƒK„!„TiIN2K+eNTyL(®a<e6¶Haa+L¤ŠR œ K L‡¤I*T PyL N¦eNT L. NLxeJa`p2T¶ M9ŒƒM(P G"TyUi ™¥ œ JaƒK„+„!TiIyNK<e€NTyL „¶fN,eJxe6Jtadm%aK„>UGadTª N2L‡yUI+eN¦laƒGauK*„TLNLP¤   ¡&¥ ¡ µ¢>W l9TI<K ® Up2K G¬[ #  ¡¥O¡µ¢&K L‡x iJT La m)NIƒªp,U a+LI<¬( # ¡¥ ¡ ” ¢&Gam[KNLa‡xK ª#e€aG™K*‡ Ut„†em[a+L e ªT GoK*p#pI*TtltK<G"N2K+ea „<¥ H

(16) <5&+

(17) &  M ŒƒM[N6„²K L[N2m[ tT G©e€K+L e&m%T ‡NªN6a<GT ªeJaBK„±„T I*N2K+eNTyL¤®ta<e#¶qaa+LxŠR œ K*L‡¤IT PL N eNTLWyK L . NL ltauG„±adK*„+„!TIN2K+eNT Lf®a;e€¶Haa+Lxe6Jake€¶HTx¶HK*„T ®t„!auG#l a ‡¤TL&p¦¬(N2LfeJa`pT ¶‰M ŒƒM¤PiG>TU &¥<Še N6„² T„±„+N¦®pake6JK<e JNPJ[IT P LtN¦eN,ltaƒG>a„±a<GladK m%T LP­e6JtadJN2PJ)MŒ}M[NL‡N,l9N2‡UKp„o Ga<lta+L9e6„e#Jaƒª#ULI;e©NTyLKp m[K L&Nªa„†e6K<e€NTyL„0T ª K e#Ja GT„IpaGT„N„;¥ –(a<G®Kpm%a<m[T G¬f¶HK„L&Tye9T La`T ªe6J&aƒIT PiLNbe€Nlaƒ‡T m[KNL„0K„±„T INK<e6a*‡x¶fN¦eJxŠR œ ¥. µ.

(18) A+

(19) <>

(20) |ƒaGa<®G"TylK„!I+U&pKG‡N2„+a K „aN6„NLI<G"a<K „+NLPp¬(NL9l9a„´e©N,PK+e€a<‡fK„BI K+U„†Kpp,¬(p6NLhta<‡­e€T¤I TPyLNeN¦la HAL author manuscript. Nm[ KNGCm%a+Lye K<Lt‡¤‡a<m[a<L e€NK ¥¦Z œ JtadK*„+„†TI*N2K+eNT Lf®a;e6¶faa+LxlK„!I<UpK<G ªK*I<eTG„KL‡¤I TPyLNeN¦la`Nm¤ K*N2Gm%a<L e]«~ K*L‡¤‡iaum a;L e©N2K.  . N2L[Tp6‡ a<G„>U® ±aI;e€„N6„²¶fa*p2pa„CeK ®pN#„>Ja ‡¥ œ JN6„²K*„„!TIN2K+eNbT LxJK*„K*p#„!T­®taa;L(a<V pT G"a<‡(N,L. m%N6‡ ‡padKPta<‡(„†U ® ±a I<e6„K*„²G"a„a K<G"I;J „†UPPa „†e6„²e6JK;ee6Jta„†Ui®QCI*p#NLNI<Kp JK*„aƒTª&G"a‡yUI a<‡(IT PL&N¦eNlta ªULI<e€NTyLf Ga*I<a‡ia„oe#JaƒK< i aK GCK L&I aƒT ª ‡N2K P LT„!a‡(‡ a<m%a+L eN2K¥Z>Z|ƒT m[m[TyL IuK G"TyeN‡xK*G#ea<G¬(N2L e©N,m[Kƒm%a‡N2K. inserm-00226364, version 1. e€JNI<hLa„„0 €ŠR œ ¢N#„0TyLaT ªeJaƒm[TGadG"a<Ia+L ep¬(N‡a+L eNªN#a ‡­lK*„!I<Up2K G&G"N#„†h(ªCK*I;eT G"„;¥ ]C\ Z€]Še N#„0Kdm[KGhaG Tª „†e6GUI<eUGKpK L‡ ª6ULI;eNbT LKpyltay„!„±ap ¶HKpp9 G"Ty taG#eNa„K<L‡fN„„+a a<L¤K*„²K*L[a<K G>p¬(N,L ‡NI<K+eT GT ªPa<LaGKpN a‡ K e#Ja GT„IpaGT„N„W Z^ T G&e€Jada<Viea+L eT ª&„Ui®QCIp6NLN2I KpK;e€Ja<G"T „+I*p2a GT„+N„<¥ Z6~ |ƒTL„!a  Ua L ep¦¬9WyNe&JKu„²KƒG"T ® U „"e Ku„„TiIN2K+eNTL¤¶fN,e6J(IuK G"‡N2TyltK„!I<UpKG ‡N„a K„±adK L‡xGN#„!h¤ªKI<e6TG„<¥¦Z  O]]oFL(K„+„±TIN2K+eNT Lf®a+e¶faa+LxŠR œ KL‡ I*T PyL N¦eN¦la`Nm¤ K*N2Gm%a<L etJK*„®a<a+L¤G"a; T Ge€a‡W ]\«Z]\ ]^ K<L‡fJK*„o®aa+L¤„!JT¶HLxe6T¤a<V e€a+L‡­e€T¤„>eG"T hiadªG>aa taG„TyL „;¥ ]~ œ JaƒTy® ±a I*e€NlaHT ªeJN6„„>e6U‡ ¬(N2„0a<VKm N2La¶`Ja•e6JaG „!TI N#T a*I<TLT m)NI`„´eK+e6U„ >M ŒƒM¢ m%T ‡iaGK<e€a„WiT G N6„²K L[aªªaI<em%T ‡NªN2aG T ª"W<eJaƒK„„±T INK;e©N2TLx®ta<e#¶fa*a;LxŠR œ KLt‡xIT PL N¦eNTyL&¥iMT INTiaI<T LtT m%N2IƒK‡ lK+Le6KPia JKu„o®aa;L(„†JtT ¶HLxe€T­®iUªªaG&Ku‡yl a<G„+aƒa<ªCªa*I;e„0T ª Ia<GeK*N2L(a;Vt T „†UG"a „W pT¶ ® NG©e6J¤¶fa*N2PJ e N„KƒmnUI+J a<Vi pT G>a ‡¤a<VK m¤ pa ¥ ]  «] w(T ¶fa*lta<G"W¶HJ&a+e#Jta<G&e6J&N„JTp‡ „oeGU adª€T9G&K*‡Up,e a;Vt T „!UG>a „G>a<m[KNL„0pN,e#e€pa a<Vi pT G>a ‡¥ MiŒƒM[N#„hLT ¶Lxe©T­®aƒK„±„!TIN2K+e€a<‡x¶fNeJ[I T P LtN,e€N,l9adªULtI*e€NTyL ] K<L‡f¶fN,e6JxŠ#R œ K<L‡¤N¦e©„ G"T PGa„!„+NT L[TyltaGe©N,m%a ¥ ] \ ^ œ JU„Wy¶fa`a;VK*m)NLtad¶Ja<eJa GeJtadK„±„T I*N2K+eNTyL¤®ta<e#¶qaa+LxŠR œ K L‡¤IT PLN¦eNTL N6„„±N2m%N#pKGN2L[‡iN,ªªaG>a L eoM Œ}M¤PiG>TU „;¥FŽªUG©e€Ja<G T ® ±a<I<e6Nla`N#„oeT(a;VKm%N¦Laƒ¶HJa<eJa<G„ a IyNªN6IdK*„ a I*e2„BT ª I*T PyL N¦eNT L(K<G"adm%T G"adK+eG>N6„†h¤ªGTm‰K<e6J a<G"T „!IpaGT„!N#„+¥<Œ0K G>p¬(„†e6U‡N2a*„²K„!„+a „+„!N,LPHeJtadK*„+„!TIN2K+eNT Lf®a<e6¶faa+L ŠR œ KLt‡¤IT PL&N¦e©NT LxU„±a<‡He#JtakRgN¦L&NyR›a+L9e6KpMieK+eakŒVtK<m%NLK;e©N2TL[ 2R¨R MyŒ0¢"W¦]\OZ]&Km%a<Ku„´UG"aT ª Pp#T ®Kup I*T PyL N¦eN¦la`„´e€K;e6U„<£*®U9em(Up,eNO &paƒm[aK„!UGa„0T ª IT P LNe€N2TL¤KGa`N2LIGaK*„†NLPp¦¬f® aNLP¤a;VK m%NLa‡¤NOL[T G‡ aGe©T N6‡ a<L e€Nª#¬¤K*„+„TiIyNK<e€NTyL „¶fN,eJ[„! a IN,ªN6IdK*„ a I<e„0T ª IyT PiLN eNT L&¥+‚ N¦LKp6pb¬9Wy¶faƒ¶fN#„†JfeT(a;V pT Gade6JtaGTp2a pK<¬ta<‡f®9¬HltK<G"N#T Ut„²G"N#„!h¤ªKI+eT G"„²K L‡¤I TtltK<G"NK<e€a„NL¤a+V pKN¦L N¦LP­eJadŠ6R œ QI<TPLN,e©NT L¤K*„„TiIN,K eNTL™¥ Ÿ.

(21) cqa„±N‡ a„„†m[T hNOLP ]C\ Z€] KL‡¤a ‡ UI<K eNTL&W ^C\«Z6]C\ ]C^ l a<GC¬(ªa¶ ITylKGNK;e©a„JK;l9ad®a*a;L[NLIpUt‡a<‡¤NLxe6Ja a<VtK<m%NLK<e€NTyL[Tª9e6J akŠ6R œ I<TPLN¦eNT L¤K*„+„!T INK<e€NTyL ¥ ³ adK*N2m‰e€T¤a<VtK<m%NLaBeJaƒa<V e©a;L ee€Tx¶`J&NbI<Jxe6Ja HAL author manuscript. Ku„„TiIN2K+eNTL¤®a<e6¶Haa+LxŠR œ KL‡(I<TPLNbe©NT L[I<K L¤®taa;Vt p2K*N2Lta<‡f®9¬f G"a;lNTU„²JN„´e€T G¬(T9ª IT G>TLKG#¬fJ a<K<Ge ‡N„+a<K „±a |wHYf¢W Ja<Kp¦e6Jx®a<JK+l NT UG"„²K+L‡(Tye#Jta<G&lK*„+I;UpKG GN6„†hfm)aK*„UGa„0p#Nhaƒ®p2TiT ‡H Ga*„„†UG"aW I JTpa„†e6aGTp K L‡­®tT ‡ ¬fmnK*„+„0N,L‡a+V ¥. inserm-00226364, version 1. <&  . YfK<e6KƒKGa‡GK¶HL¤ªG"T m‰e#J a ³ JN¦e€a<JK*p#pyŠŠ„†e6U‡t¬tWa„´e€K<®pN„>J&a ‡¤NL a<VtK<m%NLaBeJa`„TiIyNbTa<I T LT m%NIdPiGCK*‡Na<L e NLfJaKpeJ¤K L‡¤‡N„+a<K „±adK m)T LP. “‘ š K*„²K`p#TLPtN¦eU‡NLKp„´e6U‡y¬He©T ¡WOŸ¡9‘­I<NlN#p„±a<GlK L9e€„B W‘“ š. m%a<L(K<Lt‡xŸW ”o Ÿx¶HT m a<L¢†¥ ^ZFHp6pI*N,lN6p„+a<GlK L e„0K<Pta‡xŸ š Q šiš ¬a K<G"„NLxµt¡­¯}T L‡iT Lx®K*„a ‡f‡a+ KG#em a;Le€„ ¶faGa`N2L lN¦e€a ‡­eTH KG#eNIN¦ K;e€aƒ® ¬(p#a;e6ea GWyK L&‡¤’iŸ ‡UGNLP. K PGaa‡¥<c`K*„ap6N¦Laa+VKm%N¦LK;e©NT L[ 2XJK „+a. “9‘ š Q “‘ ‘tWuK L‡¤N¦LltTp,lta‡xK`Ip6N¦L NIKpa<VK*m)NOLKe©N2T L(K+L‡xK`„+apªQCK*‡9m%N¦L N„†e6aGa‡ . ¢eTiT9hf pKI a. Ua„>eNTyLiLK*N2G€a. I*TyL eK*NLNLP¤„±a<I;e©NTyL„0TyL[‡iaum T P GK+ JN#IƒI;JK*GKI;ea G>N„´e€NI„±WuJ a<K*p,e6JWp#N#ª€ay„>e#¬tp#aƒªKI;e©T G>„±Wu¶(T Gh(I<JKGKI;e€a<G"N„†e€N2I*„+W „±TIN2K*p„´U i T GeKL‡(p#Nªaa;l a+L e€„<¥*|dp6N¦L NIKpa<VK*m[NLK<e€N2TL[NLIp¦U‡a‡fm[a<K*„†UG"a<„0T9ª®p#TiT ‡H Ga*„„†UG"aW K*L e#JGT tT m[a<e6G©¬tWy®N6T I+J&a+m%N#I<K*pm[a<K„>UG"a<m[a<L e€„WLa+UGTa+L‡TiI<G"N2LaƒªULI<e€NTyLWyK L‡¤„>U ®I*p#N¦L NIKp m[KGha G>„0T ª IK G>‡NbTtltK„!I;U pKG ‡N„a<K*„a¥ MUi®„a  Ua+L9et JK„±a„T ª ‡ K+eKHI*Tp#paI+eNT L¤JK+laƒKpe€auG6LK+ea ‡H®a<e6¶faa;Lf T„´e6Kp Ua„†e6NTyLLK*N2G"adK*p#TLaƒKL‡H T„´e€Kp  U a„´e©NT L LKNGaƒKII T mn K+L Na‡f® ¬fKIpN2LNI<Kupa;VK<m%NLK+eNTyL&¥iMNLIa . ®Ku„†apNLa`„a;l9a;L¤ iJK „±a„Tª ‡ K<e6K`ITp#paI;e€NT L(JK;l9ad®a*a;L[I Tm¤ pa;e€a<‡¥ YfK;e€KdU„+a ‡¤NLxeJ adK+LKup,¬t„a„I T9m[a ªGTm eJaƒm[T„"eG"aIa+L e JK*„†a`T9ª Ip6N2LNI<K*pa;VtKm%N¦LK;e©NT L¤ 2XJK*„+aƒ’Wyµ¡i¡ŸQ#µ¡ ¡ ” ¢ I Tm¤ pa;e€a<‡x¶HJta<L G"a„! TyL‡ia;Le€„²¶faG€a š ¡Q’ ” ¬taK<G"„0Tp2‡¥ œ JaBHL Nbl9a<G„+N,e¬ |BTp2pa<Ptak¯}TL‡ TyL(a<eJ NI„I<Tm¤m%N,e6e6aadK  GT la*‡ e€Ja`„†eU‡y¬¥ H+ >nA    . “ “&¥ “. T9ªeJa š ’ ” Ÿ¤NL‡N,ltN‡yUK*p#„¶HJTfI<Km%ake€T­eJ adm a<‡NI<Kpa+VK<m%NLK<e€NTyL¤K<eXJK„!a’f¶fauGa. NL lNea ‡­e€T­e6JakltK„!I;U pKG Ip6NLN2I£<eJa`NL l Nbe€K;e©NTyL¤¶HK*„®pN¦L‡ a ‡­e©T­e6JaNG IT PL&N¦e©Nbl9adK L‡¤„!T INTa ITyLtT9m N2I ”.

(22) „†e6K<e,U&„+¥ ”oi µ[ ’yµ. T9ªe6J&T„±aN¦LlNe6a‡ ¢& KG#e©N#IN K+Le€„K;e6e6a<Lt‡ a‡­e6JaBlK„!I+U&pKG I*p#NLN#Iy¥+(peGK„±TyUL‡HlK„!I<UpK<G. m%aK*„´UGa„¶fa<G"ak taGCªT Gm%a<‡xK+ee#JaB–fK„+I+Up2K G&X J ¬„±NTp2TPy¬ffL&N¦e©WuŠL„†e€N,e6U e€aT ª |BJ&Np‡­w(a<Kp¦e6JWu¯²TyL‡iTyLxHj[¥ HAL author manuscript. Rga<K*„´UGam[a+L e„¶Ha<G"ake€K<hta<L[NL¤KBe€aum( a<GCK+e6UG>a`I<T L e€GTpp#a ‡¤ µ µQµf‡a P Gaa„0I a<L eNPGK*‡a<¢>W  U Na;eG"T T m Ut„+NLPxKƒLT LQN¦L lK„+N¦l9aWJ&NP JQG>a„±TpU eNT LfUp,e6GK„±TyU L‡(„"¬9„´e©a<m%W*e€JaƒFHp#T hK šš ¡¡x¶fN¦e#J(K’¥ š R¨w . e€GKL„‡UIa<G!¥ X KG#e©N#IN K L9e2„¶fa<G"ada+VKm%N¦La ‡¤N2L(K„>U NLaB T„!N,e€NTyL Wu¶fNe6Jxe6JadJa K‡­e6UGLta‡­e€TxK ”&š ‡aPiGaadK+LPpa. inserm-00226364, version 1. K*¶HK;¬[ªGT m‰eJa`„+N‡ake2Tx®a„!IK+L La ‡¥ŠLe€N2m[KQm%a‡NKBeJN6I<h Lta„„0 #ŠR œ ¢&¶HK„m)a K„>UG>a ‡¤NLxeJtadG"NPJ eK<Lt‡ p6a<ª#e ITm[m[TyL[I KGTye€N2‡fK<Gea<G"Na„;¥+¯}TyLPN¦e6U‡N¦LKpNmnK Pa „T ªe6J aI T m[m[T L¤I K<G"TyeN‡xK G©e€aG#¬ W<eGN2PiPaGa‡¤TLxe6Ja {qQ¶HK;l a`T ª9e€JakŒ}|`rHWu¶fa G>aƒmnK P LNªN6a‡xKLt‡xG>a I T9G‡a ‡xNLxYHŠ|ƒ˜dR. ª€T9Gm[K<eK*„BK`IN2Ltap#TiTy WTyLxe6JaƒJK G"‡. ‡ G"N,l9aƒT ªe6J&aƒUp,e6GCK*„TU L‡xm[K*I;J N¦LaƒªTG p2K+ea<G KLK*p,¬t„+N„<¥ œ JtaƒI<Tm[m[TyL[I KGTte2N2‡xŠ6R œ ¶HK„m[a<K*„†UG"a<‡xK e N,e€„ e€JNI<hiay„Ce K<Ge. Im GT VNm[Kpye€T­e6JaB®N2ª6UGIK+eNT L&¥ F m3a<K„>UGam[a+L e ¶HK„oeK ha;Lf®a<e6¶Haa+Lxe6Ja`p#a<K*‡NLP. a*‡ P a`T9ªeJa`NL eNm[KdK*L‡­e6Jadm a<‡NKdKu‡yla L eN¦eNKƒTyL[Ÿ(„a+ KGK<e€aNmnK Pa „T L(a<K*I<J[„N‡iakU „NLPfapaIeGT LNI IK*p#pN aG„KL‡­e6Jaƒm[a<K L[T ª9e€Jaxm auK*„†UG"a „²¶HK„U„±a<‡fªT G™K*LKp¬„+N„<¥ H1

(23) 2,: ƒ7C

(24) u6

(25) . |BTPLN,eN¦ltaª#UL IeNT L¤¶HK*„K„„±a„„!a‡x¶fN¦e€J¤Kƒ®K<eea G©¬(Tª&„ N,V „´e€K<Lt‡9K G"‡­e6K„†ht„WI<JT„±a;LfeTf G>TyltN‡adK I*T m¤ G>a+Ja L„N¦l aƒa;lKpUK+eNTyL T ª&IT P LN¦e©N,ltadªULtI*e€NTyL N¦LPfNL¤m%N#‡ ‡paƒKPa ‡xK*‡yUp,e©„;¥ œ Jadª€N2G"„´ee©a„†e¶HK„Kdµ¡Q¶fT G‡¤ª#G"aaGaIK*p#pyea „†e T ª !&; "  : *<$& 5t. %D ¥<X K GeNIN¦ K+L e©„ ¶faGaƒ G€ay„!a+L9e2a‡xK`p#N„†e T ªµ&¡¤TLa`T Ge¶fT¤„>¬pp2K ® pad¶fTG‡„²K+ee¶fT(„+a<I T L‡¤NL e€a<GlK*p#„KL‡f¶fa<G>aBe6Ja+L¤K„†hta‡ e©TxGaI<Kup2pNL¤¶HG"Nbe©N2LPfK„m[K<L ¬(Tª9e6J ad¶fT G‡„0N,L(K<L¬(T G‡a<G&KL‡HJK*‡­e¶fTxm%N¦LU e2a„ e©Tx‡iT¤„!T¥ œ Ja. . -CA} ©Fqp#N6Iakw(aNm ” Q#Š¢N2„0IT m¤ T„!a‡fT ª&K`„+a<G>Na„T ª  š l9a<G®Kp K+L‡xm[K;e€Ja<m[K<e€NIKp. G"a<K„!TL&N¦LP(Nbe©a<m[„0T9ª N2LI G>a<K*„NLP(‡N2ªªN6I<U&p¦e6¬¥ ^C] Šee€a„´e©„N¦L‡UI<e€N,ltaGa<K„!T LNLPWm%a<K„!UG>NOLPHe6JadK+® N2p6N¦e#¬HeT N6‡ a<L e€Nª#¬¤ K+e#e©a<GCLt„²K*L‡¤NLªaG& G"N2LI*N, pa „²K*L‡xGUpa„<¥+X KG#eNIN¦ K+L e€„²JK ‡. ¡fm)NLiU9e6a*„ e€Tf‡T­e6JN2„0„a I<e€N2TL™¥. š.

(26) œ Ja . 55. . 559–(TI<K ® UpK<G¬Hea*„†e N2„0Kke€a„´eT ªlaG®K*p m%aK+L&N¦LPfKLt‡¤a<LI Tm¤ K „+„!a„ e€JaƒK<® Np#Ne¬HeT. G"aIT PL N aƒK<Lt‡¤IT m¤ Ga+J&a+L‡f¶fT G‡„;¥«^^ ³ adU „†a*‡­eJ ake6a„´eN¦L[Ne€„m¤Up¦eN padª€T9Gm[K<e€WITL„N#„Ce©N¦LP(T ªKHp#N6„´eT ª HAL author manuscript. ŸiŸ¤„†eNm¤UpOU„¶fT G‡„T G>‡iaGa‡­® ¬(NLI<G"a<K„±NLP¤‡NªCª€N#I<U p¦e#¬fK L‡¤„NV¤Ga„> TyLt„aI+JTNIa*„<¥ ³ adU„+a ‡­e€¶HTxm%a<K*„>UG>a „BT ª: y $& 5i7>5 <

(27) *D JtTyLa<m N#IdK L‡(„a<m[K L eNI ¥ ^C~ XJ&TLam%NIªpUa;L I;¬ ¶HKu„²K*„+„a„!„±a‡­lNKyM¶qT G>‡„K L‡¤„!am[K+L eNIªpUa<LI;¬Hl NKK L&Nm[Kp¶fTG‡„;¥MUi® +a I<e6„¶fa<G"adK*„†hta<‡­e€T G"aIK*p#pNLx¶fGN,e€NLPxK„m[K<L¬f¶fT G"‡„o®aPNL LNLPf¶fN,e€JyMK*L‡xK*„m[K<L ¬fK*LN2m[Kp LK m[a„K„oeJta*¬(I*TyU p‡¥. inserm-00226364, version 1. ˜Laƒm%N,LUe€a¶HK„KppT ¶fa‡xªT Ga<KuI;Jxe©a„Ce>¥ ‚NLKpp,¬tWue6J adŸi¡QCNe€aum RR MŒ¶HK„0U„†a*‡­e6TxK„±„a „+„²PtpTy®KpIT PL N¦eNla`„"e€K;e€U„<¥«^ . 9  

(28)    MTINTiaI<TLT m%N2I`„´e€K;e6U„0 ´M ŒƒMt¢ ¶HK*„K„„+a „„±a<‡H®9¬Hc`G"N¦eN„†J[I*N,lN6p„a<GlN6I<aƒP GK‡a`T ª&am[ pTy¬im)a L eK<e ®Ku„†apNLa ¥ œ J N„N6„²KBeJGa*apa;la*pylK<G"NK®p#aƒGa< G>a „a LyeNOLPHJNPyJ  ©K*‡ m%N,LN6„´e€GCK+eN¦l adPiGCK*‡ a*„†¢"WyNL ea<Gm%a<‡NK;e€a   G"T ªa„„+NT LKup T G a<Va*I;U e©N,ltadPiGCK*‡a „†¢ K L‡¤p6T ¶  Ipa<G>NIK pTG „†U i TG#e&PiGCK*‡a„†¢M9ŒƒM ¥;X aT &pbaNLxeJtake6JG"a<a MiŒM(P GT U „0‡NªCªa G™¶fNeJ¤Ga„> aI;ee€T¤„K*p2K G¬Wi„+TI<NKp„´e€K;e6Ut„²KLt‡¤p#a+lapiT9ª&Ga„! TyL„+NO®&Np#Ne¬&¥Fqp,e6JTyUPiJ m%Ti„†ep¦¬f¶HJ&N¦e©adI Tp2pK<G"WyG"a„! TyL‡ia;Le€„I Tyl a<Ga ‡xKƒ¶fN#‡aƒGCK LPa`T ª™MŒƒMW¶fN,e€J¤K LLUKp„†KpKGN6a<„0NL. ““ š. GK LPN,LPfªG>T m ” W¦““ š e€T  *š ¡W¦¡¡i¡¥ ³ adU„!a‡He#JaB®K„!ap6NLadm%a<K*„>UGa`T9ª M ŒƒM(GCK+eJaGe€JK<L(I<UGGauL e MiŒƒM NL¤T G"‡ a Ge€TxGUpaTU9eGa<ltaG„+adI K<U„!K<e€N2TL&WNLxeJa„±a;L„!aBeJK<e tTT G&Ja<K*p,e6J¤m%NP J e p#a K‡­e2T¤p#T ¶qauGa*‡nM ŒBM ¥. Hy:9  . |BT lK G>NK;e©a„0N,LtIpU‡a ‡x Ga;lKpa+L9e |wHY(W<lK*„+I;UpK<G GN#„!h¤ªKI<e6TG„²K*L‡xJtauK*p,e6Jf®a+JK+lNTUG„<¥ |wHY G"a;lKpa+LIaBU xe€T­XJK„±ad’f¶HK„²®K*„a*‡xTL[Ip#NLtN#I+Kp6p,¬Hla G>N#ªN6a‡¤a<lta;Le6„KL‡¤NLtIypOU‡ a ‡ ªK+eK*p K*L‡xLtT LQ#ªK;e€Kp9m¤¬tTIK<G"‡N2K*pN2LªK G"I;eN6TyL[ #R¨Š¢ KL‡f‡aªN2LtN,e€adK*LPNLK ¥+R¨Š ¶xKu„‡aªNLa‡fK„K`IyT GT LK G¬(‡auK+e6J  Š|Y›“¤IT ‡ a*„ ” ¡ ” ” T G&Š"|Y TL¤Kp6p K;lK*N#pK®pa‡ K+eK` CªG"T m . ¡¤I T‡ a*„²Šµ ¡Q#µ š ¢ TG&LtT LQ©ª6K<eKpyRSŠ laGN#ªN6a‡¤NL[Ip6N,LNI<K*p<GaI TG‡ „<¥+c`K„a‡ Uta„"e©NTyL LK*N2Ga„W„†e6U‡y¬HŒ}|ƒrf„WJT „> Nbe€KpK*I<U e€akŒ}|ƒr„±W I<KG‡NKI`a;L  ¬ m%a„+W .

(29) iJ9¬t„+NINKL¤Ga*I<T G"‡ „¢WLTL&Q#ªK+eK*p9R¨Š¶xK*„‡a<ªNLa ‡ ªTppTy¶fNLP­Rg˜d‹HŠ"|BF I<G"Nbe©a<G"N2K¥ ^ |ƒp2Ku„„NªNIuK+eNbT LT ªRSŠ K*L‡xK LPtNLKd¶HK*„BI<K GG>Na‡¤TU e®pN,Lt‡­e€T¤Tye6JaG „>eU‡ ¬(‡ K<eKuWyNL‡ a< ta;L‡a+Le6p,¬}® ¬xe6¶fT­e€GKNL&a ‡¤ITi‡ aG„+W¶fN,e6J HAL author manuscript. Ku‡ †Ut‡NI<K<e€NTyL¤®¬fKBe#J NG>‡(N,Lfe#Jta GCK*G>a<¢ia<la+Le T ª ‡N#„!K<PGaa m[a<L e¥F`LPN,LKqNLIpU‡ a*‡x K<GeNbIyNO K Lye©„²¶`JT G"a< tT9G#e©a<‡B„†¬im[ e6T9m „T ªKLPNLKW ^  ¶fN,e6J[I*T GCGT®T GK;e©NTyL(N,L IypNLNI<Kp G"aIT G€‡„T G K<®iLT GCm[K*p#N¦eNa„0TyL¤K G"a„†e€NLP­Œ²|ƒrxWa;V a<G"IN„!akŒ}|ƒrHW T GIT G>TLKG#¬}KLPNT PGKm4¥ –fK„±I;U pKG&G"N2„hfm%a<K„>UG"a„ ¶fa GaHI<T m¤ GN#„!a‡(T ª&„†¬t„†e€Tp#NIB®pT T ‡f Ga„±„†UGa` CM cX ¢Wi‡N2K*„†e€Tp2N6IB®p2TiT‡. inserm-00226364, version 1. G"a „+„´UGa #YHcƒX ¢"Wy„+a GCUm I;JtTpa„>ea G>Tp K L‡x®Ti‡y¬fm[K„„0N2Lt‡a;V[ 2c`RŠ¢¥+cHp6TT ‡H Ga*„„†UGaƒ¶xK*„m[a<K„>UGa‡ e€¶fNIaNLxeJa„±N,eeNLPH tT„±Nbe€NTyL(Kyªea<G š m%NL Ue6a„G>a „´e ¶fN¦eJ¤K L¤K U eT m[K<e2a‡¤˜m[GT L¤“¡i’¤‡ a<l9N2„!a ¥ œ Ja K la<GK<Pa`T ª9e€¶fTxm%a<K„>UG"a„¶HK*„ e€K<ha+Lxe€T­®aBe6Jadm%a<K*„>UGa*‡­®pT Ti‡x Ga„!„†UGa ¥MaGUm I<JtTp#a „†ea G>Tp ¶HK„ m%aK*„´UGa‡x¶fN¦e6JNL¤’µ¤JTyUG"„0N,L „†aGUm@„†e6T G"a ‡xK<e ” |¨Ut„+N¦LP¤a+L  ¬im[K;e©N#II TpT G>Nm[a;e€GN#Idm%a;e6JtT‡ „;¥ cƒR¨Š ¶HKu„I<Kup2I Up2K+ea ‡xK*„¶faNPyJ eN¦L¤hNpT P GK m)„}‡N,lN‡ia<‡H®9¬fJa*N2PJ9e NL¤m%a;e€a<G"„0„   U K G"a<‡&¥ ³ aNPJ e&¶HK*„²m%aK*„´UGa*‡ Ut„+NLPxKƒ®NT¤N2m[ ta<‡K+LIa`„IK*p2a`  œ K+LN¦eK ¢eTfGauK*‡x¶faNP JeeT­e€JaBLaK<G"a<„†e9¡¥ hiP&¥;w(a*N2P J e¶HK*„m)aK*„†UG"a<‡HeT e€JaƒLa<K<G"a „†emnm Ut„NLPfKH„´e€K‡NT m[a<e6aG&¶fNe6Jxe6Jak K G©e€N#I*N, K L e „†e6K<Lt‡NLP¤IT m( p#a+eap¦¬(aGaI;e¶fNeJxeJaƒJa<K*‡ NLxeJaB‚ GCK Lhª#UG#e p,K*Lat¥ w(aKpeJ¤®a+JK<lNTyUG"„ ¶fauGaƒK„!„+a<„±„a ‡­U „!NLPxKpITJTpI<T Lt„>Um¤ e©NT L¤K L‡¤„m T hNL P&¥*FHp#I*T JTp I*TyL„†Um( yeNTL¤¶HK„0K„±„a„±„†a*‡­lNK . Ua„´e©NTyL„0T LxeJaƒL Uimn®a G T9ª Kp6IT JTpN#Iƒ‡ G"NLh„0  m%a<K„>UGa*„ `  T ª „† NG>N¦e©„W. *Pp2K*„„±a„ q  T ª¶fNLaWuK*L‡ &NOL e„ H  T ª®&a a<G¢ ITyL„!U m%a‡¤N¦Lfe#Ja`p2K*„´e „±a*lta<L(‡ K+¬„;¥ œ JN#„¶HK„0ITL la<Ge€a‡­e6T LiUm(®aG T ªULNe„TªKp6IT JTpI<TL„>Um%a ‡¤NLxeJ apK„Ce¶faa<h&¥*|BUGCG"a+L e „!m[T hN¦LPx¶HK*„²Ku„†„+a „„±a<‡H®¬He#J a . Ua„†e6NTyL,Y(T­¬tTU[„†m T haI*N2P K*Ga;e#e€a „²LT ¶ X KG#e©N#IN K+Le6„¶¤a<GaHI K;e€a<PtT G>N„a ‡xK„K`I<UGG>a+L e „!m[T ha G N#ª9e€Ja<¬. G"a< p6N2a ‡¬ta„#¥. t> "> 5t9

(30)  5D + FH„0N,e N6„²¶fN6‡ap,¬fKuII<a ea ‡­e6JK;e„´e€GT9hiaBJK„K<L¤K*‡yla G>„±ada ªCªaI+e TL[I<TPLN,e©Nbl9adª6ULtI;eNTyLWO^K*p#p K*G#eN#I*N, K+Le6„¶HJtTxG"a; tT9G#e©a<‡xK*L a<la G ‡TI+eT G‡NKPLT„!N#„0T ª „´e€GT9htadK+eXJK„!ad’f¶fauGa`a<VI*p,Ut‡a<‡fªCGTm e€Ja ’.

(31) K*LKp¬„+a „0 €‹ ‘‘¢>¥<Y(a*„I<G"N 9e€N,ltaƒKLKp¬t„a„K„KªULI<e€NTyL(T9ªM ŒƒM¤¶faGaIK GCGN6a‡fT U eKL‡­e€a„>e€a<‡HU&„±NLPfI<JN#Q „  UKGaƒKLK*p,¬t„+N#„ªTGeG"a<L‡xª€T9GI<K<e€aPT G"N2I Kp lK G>NK<®p6a„K+Lt‡­®¬¤ªNeeN2LPfK`p#NLa<KGe#G"a<L‡xUt„NLPfFd‹ ˜d–¤F ªT G HAL author manuscript. I*TyL eNOLUTyU„olK*GN2K ®&pa„+¥ œ Ja`‡ N6„†e#G"N¦®U e©NT L¤ªTG&ULNe„T ª&KpITJTpITyLt„†Um[a ‡x¶HK„0„†ha ¶Ha‡xK L‡He#JtaGauª€T9Ga`N,e€„ p6T P Pta<‡­lK*p2Uta Kª#e€aGe6J&aƒK‡‡N¦e€NTyL[T ª T Ltake©TxKp6pylKpUa „ e€TxG"a<m%T laBe6Ja * aGT„†¢&¶HKu„²U„±a<‡¤NL¤K*p#p KLK*p,¬t„+a „<¥ œ Jadm a<K„>UG>aƒT ª I K<G"TyeN6‡qŠR œ a+V J N¦® N¦ea ‡xKq„p#NPiJ e ‡a;lNK+eN#TLƒªCGT m LtT9Gm[Kp#¥ ³ aHI*TyL‡yUtI<e6a‡­eJa K*LKp¬„+a „¶fN,eJ(K+L‡x¶fNeJTU9ee€GKL„!ªT GCm%NLPxŠ#R œ ® UeT®„a<Glta‡xLT(N2m¤ tT G©e€K<L e ‡Nªªa<G>a LIa<„+Wp6a<K‡N¦LPHU„oeT. inserm-00226364, version 1. G"a;e€KNLxeJadLtT L­e€GCK L„ªTGm%a‡¤I TyL e€NL UTU„m[a<K*„†UG"ay¥ ³ aƒU„!a<‡xm[U p eN padK LKp¦¬„±N#„T ªITylK G>NKLtI<a  #RSFƒ‹(|ƒ˜d–¤FH¢Wye€TxKI*ITyUiL e&ª€T9Ge€JaNL e€a<GGaypK<e€N6TyLf®a;e6¶fa<a+LxeJta„+NV¤m[a K„!UG>a „Tª IT9PLNeNltaª#ULI;e©NT L¤ a G NL‡NlN‡yUKp6WN2L(T G>‡ia<G&eT(a*VtK<m%NLaBe¶qT . Ua „†e€N2TL„<¥+‚NG"„´e€W¶faªN,eea*‡xKL[N¦Le6aGKI;e©NT Lxe€aGm ®a;e€¶Haa+L)M ŒƒM. K*L‡­Š6R œ N2L(T G>‡ia<G&e€TxK„„±a<„+„¶Jae6JaGŠR œ ¶HKu„²K*„+„!TI<NK;e©a<‡x¶fNe6J¤IT PL N¦eN,ltaƒªULI<e€N2TL[N2L(K„±N2m%N#pKG m[KLiLaG NL¤Kpp&M ŒƒM¤PiG>T U t„<¥ œ Txa+L&„>UGaBeJK<ee6JaNL e€a<GKI+eNTyLxe©a<Gm ¶HK„LTye a;l9N‡ a<L e T Lp¬fK;ee€JakJ NP J a L‡¤T ªeJaBŠR œ ‡ N6„´eGN®iU9e€NTyL¤¶faƒG>a+ a<K+ea ‡­e6JaK LKp¦¬„!N#„® ¬fG"a<m%Tyl N¦LPHeJ ake6T . ¡. K L‡­µt¡. T ªe6J a. ŠR œ m%aK„!UG>a „²ªGTm eJtadKLK*p,¬t„+N„<¥MaI T L‡W¶faa;VtKm[N2Lta<‡f¶HJa;e6Ja<G Š#R œ JK‡xK L[Tyl9a<GCK*p#p K*„+„!TIN2K+eNbT L ¶fNe6J[IT P LtN¦eN,ltaªULtI*e€NTyL WK„}I;JtaI<hNLPfªT Ga<KIJ¤m%a<K*„>UG>aƒT ª I*T PLNbe€NladªULI+eNT L(„a+ K GK;e©ap,¬(NLI<G"a<K„!a „ e€Ja`I<JK+LI<a`T ª œ ¬ a. a<GGT G†¥MU®„±a  Uta;Le€p,¬tWym[Up¦eN padpNLaK<G G>a<PGa„±„+NT L¤¶HK*„²U„±a<‡­e€TxK*„+„!a„„oe6Ja. Ku„„TiIN2K+eNTL¤®a<e6¶Haa+LxŠR œ KL‡(N,Lt‡N,l9N2‡UK*p m%aK „†UG"a„T ª IT PiLN,e€N,ltadªULI+eNT L[NL¤K LK*p,¬t„+N„K‡ !Ut„†e6a‡xª€T9G K*PadK L‡¤„!a<V&¥+‚ T GeJta„aƒK<LK*p,¬t„a„±Wy¶faBU„a ‡¤„†e6K L‡ KG‡N a ‡xŠR œ K L‡¤I TPyLNeN¦laƒ‡ K+eK`  H„I*T G>a „Wm)a K<L ¡W „†e6KLt‡ KG‡(‡a;lNK;e©N2TL . ¢ NL[T G‡ a<G&e€TxKpp6T ¶ e6Jad‡NªCª€aGa<L9e I*T PyLN¦e©Nbl9adm%a<K„>UGa„e6Tx®aHI T m¤ K<G"a ‡¥ œ JtadG"Tp#a. T ªITylK<G"NK<e€a„NL[a;Vi pKN¦L N¦LPHeJaBŠ#R œ QI<TPLN,e€NTyL¤K„!„±T INK<e€N2TL¤¶HK„0a;VK*m)NLta<‡x®¬fK*‡ ‡N¦LPHe6JaƒI<TylK G>NK<e€a e©T­eJaƒm)Ti‡ apITLyeK*N2LtNLPxKPtaW „±a<VWuŠR œ K L‡¤IT PL N¦eN l aƒª#ULI;e€N2TL&¥ œ JtaITL eG"N¦®U eNT L(T ªe€JadI*TylKGNK;e©a NL[a;Vt pKN2LtNLP­e6JakŠ6R œ QCI TPyLNeNT L(K„!„TiIN,K eNTL¤¶HK„0a•V G"a<„±„a ‡xK„ aGIa+L eK PaƒGa‡yUI;e€NTyL N2Lxe6Ja G"a<PiG>a„+„!NTyL IT a<ªª"N2INa<L eªT G&ŠR œ U„!NLP­e€JaƒªT GCm[Up2K` ®a;eK ! "#

(32) . ¢ $ ®a;eK. \  

(33) %   &'%   . \  

(34)    . [®a;e€K \ 

(35)      . ¢)( ¡ ¡&¥. ‘.

(36)

(37). !5" YfK<e6K`T9LfŠ#R œ K L‡xK*p#pI TtltK<G"N2K+ea „²¶faGaƒK<lK*N#pK<®padªT GŸ‘u“ ¤NL‡N¦l N‡ UK*p#„0 ©µ‘¡‘Hm[a+L¤K L‡. ¡‘‘. HAL author manuscript. ¶fTm(a<L¢†¥*|ƒTm¤ K<G"a ‡­e€TxKp6p š š ¡¤ CT Ltp,¬ š ’ ” ŸxT ª&e6J&a „!aI<K m%ake€T­e€Ja„±I<G"a<a+L&NOLP(IpN¦L NI¢ „´e€G>T htadªGaya K*G#eN#I*N, K+Le6„K+eXJK„±aƒ’Wue6JN#„ITJTG#e NLIpUt‡ a‡xm%T Gaƒm)a+L[ ’yµ&¥ NL‡NlN‡yUKp„0  ” ¥«µ. K<PiKN2L„Ce’ ¡¥ .¢"Wyªa<¶fa GopT¶ MŒƒM. K P KNL „´e *š ¥‘ ¢&KL‡­e6JtadK<l9a<GCK PaBK<PtaTª& KG#e©N#IN K+Le„¶HK„0pT ¶fa<G ¡¥O“­¬ta<KG„. K*P K*N2L„†e ¥ ¡’­¬ta<KG„¢>¥. inserm-00226364, version 1. |JK<GK*I;ea<G"N#„>e€N2I*„T ªeJa`„†e#Ut‡y¬f K GeN6IN K<L e€„® ¬[M Œ`MxK*G>a`„†JT¶L N,L œ K<®pa. ¥FŽ„+NPLN2ªN6I<KL e©pb¬. JNPJa<G   ¡¥O¡ ¡¡ ¢& GT T GeNTL¤Tª¶fT m%aLf®apTyLPia‡eTHeJa`pT ¶‰M ŒƒM¤PGT Ui &£Ÿ&‘¥«¡ š ¥ ¡. ¶qT m[a;L(KP KNL „´e. m%a;L ¥ œ Jake€a„>eªT G™e6G"a<L‡¤„>JT¶f„ e,JK+eoMiŒƒM¤¶HK*„²K„±„TiIyNK<e2a‡x¶fN¦eJxŠR œ T Lp¦¬(K<m%T LPx¶qT m[a+L¤®U e. ¶HKu„²K*„+„!TINK<ea ‡x¶fN,e,J¤Kpp9m%a<K*„†UG"a „Tª&I*T9PLN,e€Nlaª6ULI•e©NT L[N¦L¤m%a<L¤K+L‡(N,L(¶HT m[a<L&¥iM ŒƒM¤¶HK*„K*„„±TIyNK<e2a‡ ¶fNe6J[|kwHYŽ Ga<lK*p#a+LI<aƒT Lp¦¬[NL¤¶fT m a<L[ #  ¡¥«¡µ¢>¥FHm%TLP­e6JaBlK„±I<Up2K G&G"N#„!h¤ªKI<e€T G"„NL¤m[a+L&W M ŒƒM(¶HK„ Ku„„TiIN2K+e€a<‡(T Lp,¬f¶fN¦eJ[„>¬„>eTp6NI®pTTi‡­ G"a„„>UGa    ¡¥O¡iŸ ¢&KL‡(I<JTpa„>eaG€Tp   ¡¥ ¡ ¡ š ¢"Wu®U ee€Ja Ku„„TiIN2K+eNTL¤¶HK„0„†UI JxeJK;etJ&NP Ja G²MiŒƒM¤m[a+L¤JK ‡x¶fT G„+adGN6„†hf G€T9ª€N#pa„;¥F`m%T LPx¶fTm[a+LW9M ŒƒM(¶HK„ Ku„„TiIN2K+e€a<‡f¶fN,eJ „´¬t„†e€Tp#NIƒ®pTT ‡x G"a „+„´UG"a    ¡¥ ¡ ¢&KLt‡­cBR¨Š™ ©  ¡¥ ¡ ¡¡ ¢"W¶HJ&a G>a`pT9¶ MŒƒM¤¶qT m[a<L JK*‡x¶fT G"„!adG"N#„†hf G"T ªN2p6a„<¥ œ JaƒK„+„!TINK;e©NT L¤¶fN¦e6J¤Kp6I<T JtTp9¶HK*„0„†UI Jxe6JK<e®TyeJ(JN,PiJa<GM ŒƒM¤m%a+L¤K L‡ ¶fTm(a<L[I T L„>Um a<‡xm%T G"adK*pITyJtTp#¥<‚™N,LK*p#p¦¬Wp#T ¶ M ŒƒM¤¶HK„K*„+„†TI*N,K ea*‡x¶fN,eJ(JN2PJ a<G „m[T hNOLP G"a;lK*pa;LI aNL¤m[a+L[ © ¡¥ ¡¡i¡ ¢>¥ œ Jake€¶HT¤„!a<Vta„¶¤a<G€aIT m(®N¦L&a ‡xªT G ªUGe#J a<G&K*LKp¬„+a*„²K„oeJ a NL e€a<GCK*I<e€N2TLxe€a<Gm‰® a•e€¶fa<a<L „†a+V¤KLt‡­ŠR œ  © o  ¡¥ µ¡ ¢ ‡N‡HLTye „†UPPa „†ePa L‡ aG ‡NªCª€aGauLtI<a„0N¦Lxe€Ja Ku„„TiIN2K+eNTL¤®a<e6¶Haa+LxŠR œ KL‡(I<TPLNbe©NT L&¥ ŠL[T G"‡a<G&e€T¤a<VK m)NLtad¶J a;e6Ja Ge6JaBŠ#R œ QI<TPLN,eNbT LxK„!„±T INK<e€N2TL¤¶HK„0‡N2ªªa<G"a<Le NLxe6JakeJGaa­MiŒƒM PiG>T U t„²¶faƒªN,eea*‡xKL[N¦Le6aGKI;e©NT Lxe6aGm ®a;e6¶faa+LxŠR œ KL‡[M ŒƒM[NL¤KBRSFƒ‹(|ƒ˜d–¤FŽm%T‡ ap ¶HJNI<Jxe6TiT9h NL e€TxKI*I<TUL ee#JtaNL ea GCGapK<e€NTyL „´JNO ¤®a;e¶qa<a+Lxe€Jafm[a<K*„UGa„T9ªIT P LNe6NTyL¤U„±a‡¥ œ J N„BNL e€auGKuI;eNT Lfe6aGm    ¡&¥ ¡ µ¢ „UP Pta„´e€a‡HeJK+ee6JadK„!„±T INK;e©N2TL¤®a<e6¶Ha*a;LxŠR œ QI*T PyL N¦e€N2TL¤¶HK*„B‡N#„!„+Nm%N#pKG NLxeJake6JGaa­MiŒBM PiG>T U t„<¥ ³ aƒGau ta<K<e6a*‡­e6J&N„0K<LKp¦¬9„N#„0NL¤‡ K+eKƒ¶HJtauGaBeJtakeT . ¡. K+Lt‡­eJta<Lxµt¡. T ªe6J&aBŠ#R œ m%a<K*„>UG>a „ “.

(38) JK*‡x®taa;L a;VIpUt‡ a‡xªG"T m‰eJtadK LK*p,¬t„+N„<£<e€JaƒG>a„!Up¦e„ªT Ge€JaN2Lea<GK*I*e2N2TLxea GCm ¶fa<G"adLtTx‡NªCª€aGa<L9e    ¡&¥ ¡ µ¤K L‡H  ¡¥ ¡ ¡ ” WG"a„† a I<e€N,ltapb¬t¢>¥<‚ UGeJa G&KLKp¦¬„±a„+WK‡ !U„>ea*‡xªT GK<PtadKL‡¤„±a;VW¶fa<G"aI<KGG"Na‡¤TUye HAL author manuscript. „+a+ KGK<e€ap¦¬(N2Lxe6JaBe#JG"a a­M Œ`MfPGT U „<¥ ŠLxe6JadJNPyJ(K+L‡xNLe6aGm)a*‡N2K+eaHM ŒƒM¤PiG>TU „WRSFd‹(|ƒ˜d–fF K*LKp¬„+N„Ga+l a<Kpa‡HLTfK„+„!TINK;e©NT Lx®a+e¶Ha*a;LxŠR œ KLt‡xI T9PLNeNT L[ #   ¡¥‘µ¤K+L‡(¡¥«Ÿi’WyGa„† a I;eNltap,¬i¢!¥<ŠL e€Ja`p2T ¶ M ŒƒM¤PGTU WuŠR œ ¶HK*„„+NPiLN2ªN6I<KL e©pb¬fKu„„TiIN2K+e€a<‡f¶¤N¦eJ(I T9PLN,e€NTyL(T la<GKp6p © ¡¥ ¡yµ¢!¥ œ K<®paBµ¤ G"a<„±a;L e©„²G"a<„!Up,e€„ªGT9m G>a<PGa„±„+NT L¤K LKp¦¬„N6„I+KGG"N#a‡(TyUe „†a K<GK;e©ap,¬(NLxe6JakeJGaaHM ŒƒM. inserm-00226364, version 1. PiG>T U t„²ªT GauK*IJ¤m[aK „†UG"aƒT ª IT PL&N¦e€N,l9adªULI<e€NTyL ¥ œ Ja„!adG"a„!Upbe€„K G"ad G"a<„!a<L e€a ‡xU„NLP(„´eK+L‡ K*G‡N *a‡ ‡ K eK*WyNL[T G‡ aGe€TxKup2p6T ¶ I T9m¤ K*GK<® Np#Ne¬(T9ª&G"a<PiG>a„+„±NTyL[ITia<ªªN#IN6a;Le6„K*I<G"T „+„m[a<K„>UG"a<„BT ª IT PL&N¦eN¦l9a ªULI<e€NTyL ¥+‚ TG NL&„>eK+LI aWue6JaƒK<PaƒK<Lt‡¤„a;V(K‡ !U„>e€a‡xK*„„TiIN,K eNTL¤®a;e¶qa<a+LxŠR œ K L‡fFdw ” Q€Š"WiN2Lxe€Jap6T ¶ MiŒM(P GT U (¶HK„Q¡&¥ ” ” W Nm[ p,¬tNLP­e6JK<e TLa„´e€K+L‡ K<G"‡f‡ a<lNK;e©NT L[N¦L I<Ga<K*„a`N2LxŠ6R œ N¦Lxe€JN#„PGTyU (¶HK„ Ku„„TiIN2K+e€a<‡f¶fN,eJ(¡¥ •” ” T9ª&K`„>eKL‡ KG€‡¤‡ a<l9N2K+eNT L[‡iaI<Ga<K*„+aNLHeJtaFdw ” Q#Š„IT Ga ¥ œ K<®p6akµ „´JT ¶f„oe6JK<e ŠR œ ¶HK„LT eK„+„!TINK;e€a ‡x¶fN,e6J¤K L ¬(T ª&e6J&aƒm)a K„>UG"a<„0T9ª ITPLN,eN¦l9adª#ULI+eNTyL[NLxeJaƒJN2PJ¤K+L‡ NL e€a<GCm%a ‡N2K+e€a­M ŒƒM(P GTU „<¥*˜Lxe€JaƒT eJa<G&JK<Lt‡WNLxeJaƒpT9¶ MŒƒM¤P G"TyUi [N,e¶HKu„²K*„+„!TINK<ea ‡x¶fN,e,J¤Fdw ” Q€Š    ¡&¥ ¡¡ ¢"W<RŽN#pp w(Np#p  o¡&¥ ¡¡yµ¢"W JtTyLa<m%NI #   ¡¥O¡ ¡i9¢&K L‡¤„!am[K<LeN#IƒªpUa<LI;¬(   ¡&¥«¡ µ¢!¥+w(T ¶fa<la G>W a<lta+L[N2Lxe6Jtap#T ¶ M ŒBM(P G"T U xŠ#R œ ¶HK*„oLTyeK„±„T I*N2K+ea*‡­¶fN¦eJ(m)a m[T G©¬    ¡¥ š  ¢ KL‡­RRŽM Œz # ¡¥ “ ¢†¥ MU®t„a  U a;L e K+LKp¦¬„±a„WU L‡aG#e€K<hta;Lxe©TxK*„„a*„„oe#JtaNm¤ TG#eK LIa`T ª a;Vt &pK LK;e€T G¬HlKGN2K ®&pa„oe6T­e6Ja Ku„„TiIN2K+eNTL¤®a<e6¶Haa+LxŠR œ KL‡(I<TPLNbe©NT L¤¶fa<G"aI KGG>Na‡(TyU e TyLp¬(N2Lxe6JapT ¶‰M ŒƒMHP GTU (K+L‡¤TyLp¬ ªT G&e€Jadm[aK*„†UGa„0T ª Fdw ” Q©Š"WRŽN#pp w(Np#p KL‡­e6Jtake¶fTHm%a<K„>UG"a<„BT ªlaG®Kpªp2Ua+LI;¬¥ œ Ja*„†aƒG>a*„†Up,e2„²KGa „!JT ¶HL[NL œ K ®paŸ¥+‚ T G N2Lt„†e6K<LtI<aW G>a+l NT U„oJN„†e6T9G#¬(Tª|wHY a;V pKN¦L„0¥«Ÿ ®ta<e¶Ha*a;LxŠR œ K+L‡xFƒw ” Q#Š!W  ¥. ¶fN,eJfRSN6ppyw(N#pp#W š ¥¦‘. ª"pU&a+LI<¬¥˜dl9a<GKp6p#Wue6J aI TtltK<G"N2K+ea „0a*Vi pKNLfµ š ¥«’ T ªe#JK+e¶fN,eJfRSN6p#pyw(N6p2p6Wµ¡¥O’. T ª9e€JadK„±„T I*N2K+eNTyL. ¶fN,e6J¤ iJT Lta<m[N#IƒK+L‡. ¥ ¡. ¶fN¦e6J[„!am[K<L e€N#I. T ªeJadK*„+„!T INK<e€NTyLf®a;e¶fa a<LxŠ6R œ K<L‡fFdw ” Q©Š©Wyµ ’¥¦‘. T ªeJK+e&¶fN¦eJ( JTyLtam)NbIdªp2Ua+L I;¬fKL‡(Ÿ Ÿ¥ ¡. ¶fNeJ[„±a<m[K<L e©NIªp2Ua+LI;¬¥. œ JaƒK„±„!TINK<eNT Lf®a;e€¶Ha a<L¤Š#R œ K+L‡¤I T P LNe€N2TL¤G"a<m[KN¦L„0„N2PL NªN2IK L e&K ª#e€aG™K*‡ †U„>em[a+LeªTG&Kp6p I*TylKGNK;e©a„²ªT GFdw ” Q#Š!W<RgN#pptw(Np6p KL‡x JTLam%NIªpUa;LI+¬&¥ ¡.

(39) 6 †+

(40) œ JN„o K a<G& G"a „a+L9e€„oe¶HTfha<¬¤ª€N2L‡N¦LP „+¥<‚NG„†e€W I<KGTye©N#‡HK<Ge€aG©¬ N2L e©N,m[K`m[a‡N2KBe6JNI<hL&a „„0NL HAL author manuscript. „†e6G"T hiayQ#ªG"aadm%N#‡i‡paQ©K Pa ‡¤NL‡N,l9N‡yUKp6„ #K<l9a<GK<PaƒK<Paƒ ¡¥ “ ¢N„²K„±„+T INK;e€a‡f¶fNbe6J[I TPyLNe€N2TL¤T Lp¬fK<m%T LP e€JTi„+ad¶fN,e,Jxe6Jadm%T„>e „T INTa*I<T LtTym%N#Iƒ‡N„K‡ylK+L e€K<Ptay¥ œ JtN#„Ga„´U p e N6„²ULp6N,hiap,¬He€Tx®ta‡Uake©T­ tTT G&JaKpe6J p6a<K*‡N,LPHeTf„!TINTa<I*TyLTm[NIƒ‡N„K ‡ylK+L e€K<PtadK*„ e€Jadm%aK „†UG"aT ª MŒƒM¤U„!a‡¤NLxe6JtaK<LKp¦¬9„a„ Ga<‡ K ea*„ e6Ja Tye6JtauG m)a K„>UGa„® ¬fKL¤K+laGKPtaT ª. ’H¬aK G>„+¥ Ma*ITyLt‡W<ŠR œ N2LxeJ N„²m%N‡ ‡paƒKPa‡fP GT U N#„oLT e. inserm-00226364, version 1. Ku„„TiIN2K+e€a<‡f¶fN,eJ(aNeJa<G „JtT G©ee©a<GCm l a<G®Kp m%a<m[T G¬(T Ge6J adm[a K„!UG>aƒT ªPp2T®K*pI T9PLNeNlta„†eK+e6U„  #R¨RŽMŒ0¢>¥FHª2e©a<GoK*‡ Ut„†e6m[a<L eªT G& Ga<lK*p#a<L e |wHY(WultK„+I+U p,K*G&K<L ‡H®a+JK+lNTyUGKp G"N„h¤ªKI;e©T G>„±WuŠR œ N„ „+NPiLN2ªN6I<KL e©pb¬fKu„„+T I*N2K+ea ‡x¶fNe#Jfe#Jaƒm[a<K*„†UG"aƒT ª NL‡ UI;e6N,l9adG"a<K„!TyL N¦LP¤ #Fƒw ” Q#Š"¢>WlTIK<®iUpKG#¬[ #RŽNp6pyw(N#p#p¢ K*L‡­e€Jadm a<K„>UGaƒT ª& JtT La<m[N6IdªpU&a+LI<¬¥ œ JN„N6„ e6JtadªN2G"„†e „´e€U‡ ¬He€T¤a<VK m)NLtaa<Vi p#NIN,e€p¬HeJaƒK„+„!TINK;e©NT L¤®ta;e¶qaa;LfŠR œ KLt‡¤I T9PLNeNT L(K„ K`ªULI;e€NTyL[Tª9e€Ja­M ŒƒM(Tª9e€Jad KG#e©N#IN K+Le6„<¥ ³ aƒG>a aKea ‡­e6JadK LKp¬t„+N2„}N,L N,Lt‡N,l9N2‡UK*p„²¶fNe6J[pT ¶HaG&Š#R œ ® ¬(Ga<m%T lNLP­e6JaBeT . ¡. KL‡­e6Jta;L¤µ¡. T ª9e€JakŠR œ m[aK*„†UG"a<„0NL[T G"‡ a<G&e€TxGUp2aƒTU9ee6JaB T„!„N®N#p6Nbe6¬. e€JK<eeJ adGa„>U p¦e„¶Ha<G"adKL(K<Ge€auª6KI;e Tª&K*„+„T INK<e©NTyL„K;ee6Jaa;VieG"a;m%a „BT ªeJakŠR œ ‡N„†e6G>N® U e©NTyL&¥ ³ a T®9e6KNOLa<‡¤„+Nm%N#pK<G G>a„!Up,e€„ªT Ge6JaHa+Lye©N2Ga‡N„†e6G"N¦®U eNT L Tyªe€JakŠR œ „!I T9GaWIT LªNGCm%NLP­e6JadGapN2K+® Np#Ne2¬(Tª TUG G>a„!Up¦e„<¥ œ JiU&„±W N¦eK a K<G"„ e€JK;eM ŒƒMWJa<G"adm a<K„>UGa*‡x® ¬(a<m¤ pT ¬ m%a+L9ePiGCK*‡aWN#„KL[Nm¤ T G#eK Le m%Ti‡a<GCK+eT GT9ªeJaƒK„+„!TINK;e©NT Lx®ta;e¶fa a<LxŠ6R œ KLt‡xI T9PLNeNT L&¥ FŽm)T‡a GK<eT G  T G&KL a<ªCª€aI;em%T‡NªN#a GC¢ N6„²K ltKGN2K*®p2a¶HJta<G"ake6Ja`‡ aP G"a<aƒT ª K*„+„T INK<e€NTyLf®a;e¶fa a<L¤K+L a;V tT „†UG"adK L‡xK+L[TU9e2IT m[akltKGN2K ® paI<JK LPia„ KuII<TG‡N¦LP­e2T¤N,e€„²ltKpUa ¥ œ Jakl9Na<¶ e6JK+e MŒƒM¤m[K+¬fKI;eK„Kƒm)T‡a GCK+eNLP­ltK<G"N2K ®padJK*„²®taa;L „´JT ¶`L¤¶fN,e6J(Tte,Ja<G&J a<Kp e6J TU9e2IT m[a„W¦^ «~†ZKL‡¤N„Kp6„!TxG>a Ga„!a<L e2a‡¤NLxe6JaLtTyeNT LfT ª IT PL Nbe€NladG"a „+a<G#lay¥ ~]¦~~|ƒT P LN¦eN¦laƒGa„†aG#l a IK+L¤®G"T K*‡p,¬f®a`„!aya+L¤K„oeJaƒK<® Np#N¦e#¬(T ª&K L[NL‡N,lN‡UK*pye€T­e€Tp2a GCK+eaƒ G>T PiGa„„±N,ltad®GKNLx K eJTpT Py¬f¶fN,e€JTU9e m[KLNªa„†e€K;e©NT L[T ª Ip2NLNI<KpI T9PLNeN¦ltaH„´¬im[ 9e2T9m[„+¥+w[NP J%M9ŒƒM(T G a*‡yUIK;e©NTyL[N„}T ª#eaLfU„!a‡xK*„²Kƒ GTtVi¬¤ªT G I*T PyL N¦eN¦laƒGa„†aG#l aƒK<Lt‡x„+a a<Lxe6Tf®UªCª€auGe#J aa ªCª€ayI+e„0T ª&La;UGTy K+e#JtTpT P ¬(N,L „†UI J¤Kƒ¶HK<¬HeJK<ee6J adPiG>a<K e6aG .

(41) e€JaƒG>a„±a<GlaWe#Jaƒm[T G"a„!a<la G>aBeJaB K<e,JTp2T P¬fm[U&„>e®a}e€T¤IK+U „!adªULI<e€NTyLKpNm¤ KNGm)a+LeC¥ œ JaƒITLIa; e T ªIT P LNeNltadG"a„a<Gla`IK+Lx®aƒ„+a a<Lxe6Tx®a`I<T m( T „a ‡¤T ªe6¶fT¤apam[a+L e„<¥ ~~ œ JaƒªNG„†eWye6J aB K„!„+Nbltam%T ‡iap2W HAL author manuscript. „+a a „Ga„†a G©l9adK„®aN¦LP¤pNLha ‡­e©T­®GKNL[I<K+ K INbe6¬¥ œ J Ut„+WK‡aI p#NLa`T ª I<K K*IN¦e#¬He€TxKHI*a<G©e€KNLxe6JGa„!JTp‡ Ltaa ‡„oe6Tx®aƒGauK*I<Jta<‡xªT G„ aIN2ª€N#IªULtI*e€NTyLK*p TG Ip#NLNIK*pI T P LNe€N,ltaƒ‡a<ªNIyN¦e©„ e©T¤a;m%a<GPia ¥ œ J aƒKI+eN,lta m%Ti‡apT ª&G"a„aG#l a„!aa*„auªª"NIN2a LI<¬(T ª&L a;UGKpLa+e¶HT Gh„KLt‡xKI<e€N,ltaHI T m¤ a+L„K+eNT L¤® ¬fKupbe©a<GLK;e©N,ltaT G m%T G"aƒa;Ve6a<L„+N¦laBLa;e€¶HT Gh„Kª2e©aG ‡N#„±auK*„!aT G NL„†Up¦ee€T­e6Ja`Ia;Le6GCK*pLa<GlTU„„>¬„´e©a<m‰e€Tx GT lN‡ia. inserm-00226364, version 1. G"Tye€a<I<e€NTyL¤K*P KN¦L „´ee6JtadªUL I;e€NT LKpI TyL „†a  U a LI ay„T ª La+UGT K+e6JTpT P ¬(NLxea GCm%„T ª ‡apK;¬9NLP(T G G"a;l9a;Le€N,LPHe6Ja`‡ a<e€a<I;e©NTyL[T ªe6Ja`‡N2„±a<K*„aWGCK+eJa<G&e6JK+Lx G"Tye€a<I<e€NLPxKPiKNL„†e9‡N#„a K „+adK*I  UtN#„+N¦eNT L Nbe€„±ap2ª¥ ¯}T¶ M ŒƒMWK„Kd G"TyV¬(Tª&„m[K*p#paG ITPyLNeN¦laƒGa„†a G©l9ayWN6„pN2htapb¬He©Tx®aHNOLIGaK„+N¦LPp¬(„aa+Lxe€Tx®tadKƒG>N„h ªK*I*e€T GªTG ‡am[a;L e©N2K¥<ŠL[ª#KuI;eWKG"aIa+L e&K+e#e€a<m¤ ee©T­ G"a ‡NI<e9‡aum a;L e€N2KƒK m%TyLPxm%N‡‡ p6adK P a*‡¤NL‡N,lN‡UKp„ Tyl9a<G&µ¡­¬taK G>„0T ª ªTp#pT9¶fQ#U (GN#„†h(ªT UL‡fa<‡ UI<K eNTL¤KpT LPf¶fN,eJ(KPaWPa<Lt‡aGWy®pTTi‡x Ga„„>UGaWu®tT‡y¬ m[K„±„NLt‡a*V9W I+JTpa„>ea G>Tp6Wu iJ9¬t„±N2IK*p KI;e©Nbl N¦e6¬fK<L ‡xFdX™˜dŒza ” „†e#K eU&„oe6TxG"ap6N2K+®p,¬f G"a ‡NI;e ‡iaum a;L e©N2KƒK<L‡ ¶HKu„²U„±a<‡­e€T¤a*p2K+®TGK<e€adK`‡a<m a<L eNKƒG>N„h(„IT G"ay¥ ~  } Œ ‡ UtIuK+eNbT L[N„TLadTªeJadm[Upe6N p#aNLt‡N2I K<e€T G„BT ª™MiŒM&¥ ³ aa;VK m%N,Lta<‡(„+N,V ‡ N2ªªaG"a<L e m[a<K*„†UG"a<„0T9ª ITPLN,eNbT L „†JtT G©ee©a<Gm l a<G®Kpm%a<m[T G¬tWN,L‡UI<e6N,l9a G"a<K„!TL&N¦LP( ©Fƒw ” Q#Š>¢Wyl9TIK+® U p,K*G#¬[ #RŽNp#p6Q2w(N#p6p,¢´Wuµ(m)a K„>UGa„0T ªl a<GC®K*pª€p2Ua<LtI;¬fKL‡xKƒm%a<K„>UGadTª I*T PyL N¦eN¦la`„´e€K;e6U„} 2R¨R MiŒ0¢†¥+RŽTi„†e „´e6U‡Na„oe#JK+e JK;l9aaVKm%NLa<‡HeJaƒK„!„TiIN2K+eNTyL(®a<e6¶Haa+L¤ŠR œ K L‡ I*T PyL N¦eNT LfJK<l9akU„±a<‡fm[aK„>UGa„T ªPpT9®K*pI<T PiLNbe€Nla`„´e€K;e€U„0„†UI+J¤K„oe#JtakRzR MiŒ}W ]\«Z]\ ~ >\ ~ ¶HJN6I;J(‡ Ta<„ LtTteKu„†„±a„„}„´ taINªN#IƒK„ taI;e€„0T ª&IT P LN¦e©N2TL&¥˜UG&G"a„!Up,e6„B„>JtT9¶ ŠR œ LTyee6Tx®a`„NPyLNªNIuK L e€p,¬fK*„+„TiIyNK<e2a‡ ¶fNe6Jxe6JakRzR MŒKLt‡xm[a<m[TG#¬&¥ œ JadG"a<„!Up,e€„GapK<e€NLP­e€Txm%a+m[T9G#¬(KGaƒUL&„>UG# GN#„NLPfK„oe#Jaƒa;Vt a<I<e6K<e€NTyL N6„ e€JK;elK*„I+U p,K*G&GN#„hfªCK*I<e€T9G„K G"adLTyeLtaIa „+„†K G>N6p¦¬fG>apK;e"a ‡­e©Txm[a<m[TG#¬&¥ ^ ˜UG G"a„†U p¦e€„TLxe6JadRRŽM Œ I*TyUp‡x®aƒa<Vi p2K*NLa‡­® ¬He€JadªK*I;ee#JK+eeJaGa`N#„0p#N¦e#e©paklK G>NK<e€N6TyL[NLxe6JakRzR MŒz„!IT G"a„NL[TUG„†Kmf &pbayW m%Ti„†e N2L‡N¦l9N2‡UK*p#„K+ee6J N„²K*Pa K+l a<GKPaƒKPa` ¡&¥ “9¢„ITG>aƒJN2PJp,¬(T Lxe6JtakR¨RŽM Œ`¥ œ JaƒK„!„T INK<e€NTyL „  >M aK GCm[K L¤I T9GG"apK;e©N#TyL¢ ®a;e¶qa<a<L%M ŒƒM¤K L‡xm[a<m T G©¬  ©G ¡&¥ “ ¢T9Ge€JaBR¨R MŒz #G   ¡¥ “¢&¶fa<G"ad¶fa<K*h aG ¶HJa+L[I T9m( K<G"a<‡HeTHeJaƒTye6JaG&m%a<Ku„´UGa„0T ª&IT PL Nbe©NTyLfU„a ‡xJaGa<Fƒw ” Q©Š  ©G  ¡¥ ” “ ¢"W<RŽN#pp w(Np#p CG  ¡¥ š µ¢"W µ.

(42) iJTyLtaum%NIH #G   ¡¥OŸ ¡¢WKL‡(„+a;m[K L9e6N6IdªpU a;LtI*¬( G o  ¡¥ Ÿ š ¢>¥iFdeeJN6„„>eK PaWNe N#„ULIpa<KG&¶HJta*e,J&a<G„T m[a „! a<INªN#Iƒm%a<K„!UGa„Tª ITPyLNe€NT L¤K G>aƒ K<GeNI<UpK<G"p¦¬HlUp,La GCK ®pake€TxK+eJaGT„±I<p6a<GT„+N„BT G Nª N,e N6„ ! U „´ee6JaNG HAL author manuscript. PiG>a K<e€auG K„„±TI<NK;e©N2TL¤¶fN,e6J)MiŒƒMxe6JK<e N#„o®taN¦LPf NI<hia‡xUi [NLxe6JadK*„+„†TiIN,K eNT Lt„²¶fNeJ¤ŠR œ ¥ œ JadK*„„!TINK<e©NT L„o®a<e6¶faa+LxŠR œ KL‡fIT PL&N¦e©NT L¤¶fadGa TG#eKGa„m[K*p#p ®U e IT m¤ K*GK®pake6T­e€JT„!a G"a< tT9G#e©a<‡H®9¬(Tye6Ja<G„>e#Ut‡Na„TL[„´e€G>T hiaQ#ªGayaƒm%N‡‡paQ©K Pa*‡¤NL‡ N,l9N‡yUKp„<¥Z]\ ]^ ³ JN#p#aBeJ adm[a I;JK LN2„m „ UiL‡ aGp,¬tNLP­e€JN2„K*„+„†TiIN2K+eNT L¤Ga mnKuN,LHeTH®aHa+V pNI<K<e6a‡iWN,e N#„ p2K U „N®p6ake6JK;e GT P G"a „+„N,lta`T IIpUt„+NT L[T ª. inserm-00226364, version 1. K*G#ea<G"Nay„0NLxlK*„+I+Up2KG ‡N„±auK „±aN„0p#N2htap,¬He©T¤N¦L I<pUt‡adTI IpU„+NTL[T ªe6JaHI<a G>a+®GKup K<Gea<GN6a„Ga„>Up,e©N¦LP(N¦L I*a<G>a+®GKp e€N#„„!Ua`p#T „+„K+L‡fIT P LNeNltad‡a*IpN,La¥<ŒlN‡ia<LI aTª9e€Jap6N¦Lhf®a+e¶Ha a<L[Nm¤ K*N2Ga‡¤I T P LNe€N,lta ªULI<e€NTyL[NL¤m%N‡ ‡paƒK<PaƒK<L‡¤„>Ui®„†a  Ua<L e9‡a<m[a+L9e€N2K*W \ Z \«ZCZ p#a K‡„oU„oeTH®apN#a;l9ake6JK+ee6JadGa„>Upe„Ga< T Gea ‡ JtaGaK<G"aIp6N¦L NIKp6pb¬fG"ap6a;lK<L e"¥ œ J U„+WK;e6ea<m( ye„oe€TxU„±akltK„+I+U&pKG GN#„hf GT9ª€N#p#a*„ e©T­ G"a<‡NI;epK<e€aQp#N2ª€a ‡iam[a;Le€N2K`N2Lf a T paT ªm%N#‡‡padKPta ~  T UPJee€TfITyL„+N‡ a Ge6Jaª6KI;eeJK eKI*auG#e€KNL¤G"N„hx G"T ªN6p#aƒm)NPJ e JK laƒK`‡NªªauGaL em[aK+L N¦LP[NL(‡N2ªªaGaL e M ŒM(P GT Ui „<¥ œ JadGa„>Upe„Ga< TG#ea ‡HJaGaLa a‡­e€TH®aNL9e2auG6 Ga<e6a*‡x¶fN¦eJ¤K`ªa<¶ N„+„>U&a „NL¤m%NL‡¥+‚ N,G"„´e©W ³ JNea+JKpp ŠŠ N#„K`„´eU‡ ¬(TyL N2L‡iN,l9N2‡UKp„¶JtTxJK*‡¤„´e€K+®&paƒ¶HJ&N¦e€aQI<Tpp2K G  T ®t„²K+e ®K„±ap#NLaƒK<L‡HeJU„‡ TxLTyeG"a+ Ga„±a<Lye e€JaƒPa;LtauGKup T UpK;e©NTyL&¥Fq„²K`Ga„†U pbeeJa„!a`N,Lt‡N¦l N‡ UK*p„‡THLTye Ga< Ga„!a<L ee6JapT ¶Ha„>e a;Lt‡¤T9ªeJa „±TINT aI TyLT m%NI„> a I;eGUm%W<e#JaBULta<m¤ pTt¬ta ‡¤TGeJtT „aƒNL[NL„a*I<UGa ± T ®„+¥<‹(a;l a G©eJtap#a „†„+W<e€Jad„K*p2K G¬ GK LPaT ªeJaB K GeN6IN K<L e€„0Ipa<KGp¬(N2L‡NI<K<e€a„oe6JK;ee6JaH„CeUt‡y¬(N2LIp¦U‡a „Kƒ¶fN‡a„!TINTa ITyLtT9m%NI`„† a*I;eGUm4¥ M9aI<T Lt‡W ‡ K+eKƒJaGaƒKGa‡GK¶HL¤ªG"T m‰e6Ja. “

(43) &¬a KGT ª™Kq„´e€U‡y¬WNmn p¦¬9N,LPf®Tye6J[„†UG#l N¦lK*p KL‡(„apaI;e€NTyL. aªªaI+e„<¥ œ JN„N6„a;l9N‡a;L eN¦Lxe6JadG"a „†Up,e€„0TyL[I T lK G>NK;e©a<„ Ga „a+Lea*‡¤N¦L œ K+®pa. £e6Jad K G©e©NIN¦ K<Le„0N,Lfe#J N„. „†e,U‡y¬fKG>aƒKªKNGp2¬¤JaK*p,eJ¬fP GTU &¥ œ JaGaªTGaWyN¦eN„ Ti„+„N®pake6JK;ee6JaK*„„±T INK<e€N2TLx®a+e¶Ha*a<LxŠ#R œ K+L‡ I*T PyL N¦eNT L N2„U Lt‡a<G"a„´e€N2m[K+ea ‡¤NL¤TUG„†K mn pa ¥+‚N2LKup2p¬tW TyUGI<G"T„!„+Q„+a<I<e€NTyLKp G"a „†Up,e€„Laa*‡­e6TH®&a G"a< p6N2I K<e6a‡¤NOL[p#TLPNbe6Ut‡N¦LK*p‡K;e€Ky¥ ŠL[ITL&I pU„+NT LWT UG&G"a„†Upe6„„!JT ¶ IK G>Tye©N‡xKG#e©a<G¬(N,Le€N2m[K*Q©m%a‡NKke6JNI<hiLa<„+„±WyK`„Nm¤ p#aƒ„>UGG"T P K ea m%aK*„´UGaƒT9ªK+eJaGT„!IpaGT„+N„±W*e©Tx®aƒK„!„TINK<e€a‡f¶fNbe6J[„!Tm[adm%a<K „!UG>a*„T9ª ITPyLNeNT L N¦L¤m%N#‡i‡paƒKPa ‡ Ÿ.

(44) NL‡NlN‡yUKp„0N2Lxe,Ja *p#T ¶ f  M ŒƒM¤PGT Ui &¥ ³ a`N2Lye©a<G G"a;ee,Ja„!aGay„>Up¦e„oe6T¤Nm[ p,¬He€JK;eN¦e N„J&NPiJ[I<T PiLN,e€N,lta G"a„±a<G©l9adK m%T LP­e6JaƒJN2PJ)MŒBM NL‡N,lN‡UKp„oeJK<e N„ G>al a;L e©NLPxª6ULtI;eNTyLKup mnK L N,ªa*„†e#K eNT Lt„T ª HAL author manuscript. K e#Ja GT„IpaGT„N„;¥ œ JaƒK„!„TI N2K+eNTyL„¶fN,e6J[I T P LNeNTL¤KGa‡T m[K*NL[„† ta<INªN#IƒK<Lt‡­eJtadG"a„†Up¦e€„B„>UPPia<„†eLT Ku„„TiIN2K+eNTL¤¶fN,e6J(„†JT Geea GCm l a<GC®K*pm)a m[T G©¬¥. inserm-00226364, version 1. ”.

(45) (/

(46) y'f56 1i y% 

(47) " FxMQ2R. N„0„U T Ge€a‡H® ¬fK u|kJK*N2G"a‡ 6 a;VtIap6pa<LtIya   K ¶HKG‡¤ªG>T m eJad‚Ga<LI<JHRŽNLN6„"e€G©¬ T ª. HAL author manuscript. {qa„!aK G>I+J¤K L‡xK;Œ0UGT a<K LqTyU LPxŠ€L9l9a<„†e©N,PiK<e€T G&F¶fKG‡ H  ªG"T m‰e6JakŒUG"Ty taK+L)MINa;LtIak‚TUL‡ K<e€NTyL ¥. inserm-00226364, version 1. K*L‡­cqpT Ti‡­ŠL„†e€N,e6U e€a #PGK L9ewH¯}ŸiŸ ¡ ¢!£<e6J&aB‹fK;e©N#TLKpuŠL„>eN,e6Ue6aƒT L¤FPtN2LP( ©PGK*L eFHr. RzR. N#„0„†Ui T Ge6a‡x® ¬fK LxR¨{d|¨G>a„±a<K G>I+J¤ GTªa„„!TG„†JN &¥ œ J a ³ JN,e2a<JKppyŠCŠ™„†e#U ‡y¬fJK„o®aa+L[„!U T G#e©a<‡. ® ¬(P GK*L e„ª6G>T m‰e€Jakc`G>N¦e©N#„>J­Rga<‡NIK*py{`a„!aK<G"I<J(|BT U LtIyNp 2R¨{`|B¢!£<e€Jakc`G>N¦e©N#„>Jxw(aK<Ge‚TUL‡ K<e€NTyL £<e€Ja c`G"N¦eN#„>Jxw(aK*p,eJ(KL‡nMtKªa<e¬HŒV9aI<U e©Nbl9ay£<e€JacG"N,e€N6„´JfY(a< KG#em%a+L e T ªw(aKpe6J™£ eJaB‹fK;e©N#TLKpyw(aK<Ge€Wu¯0U LPW Ÿ “ ¢!£<e€Ja. F`Pa<LI<¬(ªTG&w(a<Kp¦eJ[|BK G>aBX TpNI;¬fKL‡­{`a*„†a KGIJ[ #PGKLyew[M ¡i š&  ¢!£K*L‡­eJta v T J LxY[¥ KL‡(|kK eJa<G"N¦L&a œ ¥ R›KIF`G#eJ UG‚T UiL‡ K<e©NT Lx{`a*„a<K G>I+Jx‹(a<e6¶HTGh„TyL)MtUI<Ia*„†„ª6U&pyRgN#‡pNªakY(a;l a*p2T m[a<L eKLt‡ M9TINT aI TyLT m%NI­M e6K<e6U„K<L‡Hwfa<Kp¦e6J&¥ ³ aBeJK+LhxK*p#pT ªe#J ad K GeNIN¦ K;e©N¦LP¤INlN6p„†aG#l NIaƒ‡ a K<Ge6m)aLe„K<L‡­e,JaN2G&¶fa*p2ªKG"aW &a G>„!TyLLa p#W K*L‡¤a „†e6K<®p6N2„!Jm[a<L e9T9ªªNIa<G"„;£<e€JakcqGN,e€N#„!J[˜HI<I+U K+eNTyLiKpyw(aKpe#J(KL‡nMtKªa<e¬¤F`Pa<LI<¬£<eJaBc`G>NeN6„>J |}T U LINpT ª&|ƒN,l9N#pMaG#l NIaBfLN2TL„<£*Kpp9 K G©e©NIyN K<e©N¦LP(I<NlN#p„±aG#lK<L e€„0N,Lfe#Ja ³ JN«ea<JK*p#pyŠŠ„´e€U‡ ¬£KL‡xKpp m%amf®a<G>„0T ªe6Ja ³ J N ea+JK*p#pyŠŠ „>eU‡y¬fe€aK<m4¥. š.

(48)  $5, 8&   <6†"2* 7™ `&5 0x7

(49) <>

(50) % 7o  

Références

Télécharger maintenant ( PDF - 26 Page - 371.00 KB )

Documents relatifs

Détermination quelques paramètres biochimique chez la femme enceinte atteinte de diabète gestationnel dans la région de Mostaganem

Dans notre étude des deux groupes de femmes enceintes témoins et Diabétiques , on remarque une augmentation dans l’indice de masse corporelle (IMC) des mères diabétiques

en fr

De plus, l’épaississement de la paroi des artères pulmonaires proximales a été attribué à la prolifération et la migration anormale des cellules musculaires lisses existantes, ou

Synthesis and biological evaluation of new dipyrrolo[3,4-a:3,4-c]carbazole-1,3,4,6-tetraones, substituted with various saturated and unsaturated side chains via palladium catalyzed cross-coupling reactions

Synthe- sis and biological evaluation of new dipyrrolo[3,4-a:3,4-c]carbazole-1,3,4,6-tetraones, substituted with various saturated and unsaturated side chains via palladium

The tree structure in staircase tableaux

They appear as a labeled version of tree-like tableaux (TLTs) defined in [1]. These tableaux are in bijection with staircase tableaux, and present two nice properties inherited

"Est-ce que ça marche ?" À propos du tasfih, rituel protecteur de la vertu des jeunes filles tunisiennes.

» (op. Si celui-ci appartient à une culture maghrébine, il présentera un terrain propice aux croyances et aux rites et il développera par ricochet une sorte de blocage

La responsabilité sociétale des établissements de santé en Algérie

– modifier les déchets solides dans leur apparence et leurs caractéristiques physiques pour réduire les risques mécaniques et psychologiques. Après broyage des déchets

Self-consistent coupling of the three-dimensional fluid turbulence code TOKAM3X and the kinetic neutrals code EIRENE

The coupling of the TOKAM3X 3D turbulence code with the Monte Carlo code EIRENE has been verified in the laminar mode in X-point geometry, clearing the way for simulations of

ATAT1-enriched vesicles promote microtubule acetylation via axonal transport.

To test whether the vesicular pool of Atat1 promotes the acetyl- ation of -tubulin in MTs, we isolated subcellular fractions from newborn mouse cortices and then assessed