HAL Id: inserm-00165788
https://www.hal.inserm.fr/inserm-00165788
Submitted on 23 May 2014
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Tachykinin regulation of cholinergic transmission in the limbic/prefrontal territory of the rat dorsal striatum:
implication of new neurokinine 1-sensitive receptor binding site and interaction with enkephalin/mu opioid
receptor transmission.
Sylvie Pérez, Adrienne Tierney, Jean-Michel Deniau, Marie-Louise Kemel
To cite this version:
Sylvie Pérez, Adrienne Tierney, Jean-Michel Deniau, Marie-Louise Kemel. Tachykinin regulation of cholinergic transmission in the limbic/prefrontal territory of the rat dorsal striatum: implication of new neurokinine 1-sensitive receptor binding site and interaction with enkephalin/mu opioid recep- tor transmission.. Journal of Neurochemistry, Wiley, 2007, 103 (6), pp.2153-63. �10.1111/j.1471- 4159.2007.04944.x�. �inserm-00165788�
✁✄✂✆☎✞✝✠✟☛✡✌☞✎✍✏☞✑✍✓✒✕✔✞✖✆✗✏✘✎✂✚✙✛☞✎✜✆✍✢✜✚✣✤☎✞✝✏✜✆✘✑☞✎✍✏✔✥✒✦✖✆☞✑☎✧✙★✒✕✂✆✍✪✩✬✫✭☞✮✩✯✩✬☞✑✜✆✍✢☞✎✍✰✙✱✝✏✔✧✘✑☞✮✫✭✲✳☞✑☎✵✴✷✶✏✒✞✔✕✣✱✒✦✜✆✍✌✙✱✂✆✘✸✙✱✔✥✒✞✒✕☞✹✙✛✜✠✒✬✟✰✜✆✣
✙✱✝✏✔✤✒✦✂✚✙✻✺✏✜✠✒✞✩★✂✼✘✽✩✱✙✱✒✦☞✑✂✚✙✱✗✏✫✿✾❀☞✎✫✭✶✳✘✑☞✎☎✞✂✚✙✛☞✎✜✆✍❁✜✚✣✻✍✏✔✵❂❃✍✏✔✞✗✪✒✕✜✠✡☛☞✎✍✏☞✎✍✏✔❅❄✞❆✱✩✬✔✞✍✽✩✬☞❇✙✱☞❉❈☛✔❊✒✕✔✞☎✞✔❋✶●✙✛✜✠✒✤✲✏☞✎✍✏✺✏☞✎✍✏✖❍✩★☞✹✙✱✔
✂✆✍✏✺■☞✑✍✠✙✱✔✞✒✕✂✆☎✦✙✱☞✑✜✆✍❏❂❑☞✹✙✛✝■✔✞✍✏✡✌✔❋✶✳✝✏✂✚✘✑☞✎✍✠✴▲✫■✗✭✜✆✶✏☞✎✜✆☞✎✺✭✒✕✔✞☎✞✔✞✶✌✙✱✜✆✒✄✙✱✒✦✂✆✍✏✩✯✫✭☞✎✩✯✩★☞✎✜✆✍
▼✼◆P❖❘◗✌❙✑❚❱❯❀❲✦❳✱❚✦❨❬❩✼❭✤❪✚❳✱❙❇❚✞❫✆❫✆❚❵❴❛❙❇❚✦❳✱❫✆❚✦◆❜❩✆❝✯❚❋❞❬❫P❡▲❢✰❙✑❣✞❤✆❚✞❖✼✐❑❚✞❫✆❙✮❞✵❥❜❦❋❞✦❫P❪❧❢♠❞✦❳✱❙✑❚✞❡▲♥✻♦✚❥✌❙✮♣✱❚❱q❑❚✞rs❚❬❖
t✮✉ ▼✚✈①✇✄❢✰❩③②❑④✆④✆⑤✆❩❵⑥✸♦✼❖❇❖✑⑦✦⑧☛❚⑨❪✆❚✿⑩✏❳✱❞✦❫❜❣❋❚✞❩❶❯❀❞✦❳❷❙▲♣✛❩❶⑩✳❡❸⑤✠❹✥❺❜❻ ⑩✏❳✱❞✦❫P❣❼❚❾❽✄②❅❫✆❙❘◗✢❯❀❙✎❚✕❳❸❳✱❚⑨❚✵❿❅❢✰❞✕❳❸❙❇❚⑨⑥①❥❜❳✱❙❇❚✥❩
❯❀❞✦❳✱❙✎♣✱❩✚⑩✽❡❸⑤✠❹➁➀✆➀✠❹➁❩✚⑩✏❳✱❞✕❫✆❣✞❚✚➂
❴❛❚❬❖▲➃✚➄❸❻✆❻✚➅❛➀ ✸➆✆➆ ❺❜⑤ ❺ ④ ⑩✽❞✵➇☛➈✽➄❸❻✆❻✚➅❛➀ ✸➆✆➆ ❺❜⑤ ❺s④✚➀
⑥✄♦✼❳❷❳✱❚❼♣❸➉P♦✼❫P❪✼❙❇❫➁⑧✢❞✵❥✆❿✷❤P♦✼❳✵➃➊❢✰❞✦❳❸❙❉❚✞❡▲♥✻♦✚❥✌❙✮♣✱❚❁q❧❚✞r❍❚✞❖ t✮✉ ▼✚✈①✇✄❢ ②❑④✆④✆⑤✆❩③⑥✸♦✆❖❇❖✑⑦✦⑧❜❚➋❪✆❚➌⑩●❳✱❞✞❫✆❣✥❚✞❩ ✆ ➉✆❖❇❞✞❣✥❚
❢✰❞✕❳✱❣✞❚✞❖❇❙✹❫❊➍❶❚✦❳➎❿✷❤P❚✞❖❇♦P❿❀⑤✠❹✥❺❜❻ ❯❀❞✦❳❸❙✎♣✛❩P⑩●❳✱❞✞❫✆❣✞❚✚❽P❚✞❡❸r❅❞✞❙✎❖❷➃✚r❍❞✕❳➏❙❉❚✞❡❸❖❇♦P❥✽➂➑➐❜❚✞r❅❚✞❖✑➒➓❣❋♦✠❖❇❖✎❚✕⑧❜❚✞❡❸❪✆❚✞❡❸➔✮❳✱❞✞❫❜❣✞❚✚➂→➔✮❳
❭❵➣✆➣✆❳✱❚✦◗❜❙✑❞✵❿❷❙❇♦✼❫ ➃
α❡❸r❍❚✯❿✷❤✚◆✆❖✑❡➎➉❜❡▲❿✷◆➁❳✱♦●♣✱❙❇❫P❚✞❩
α❢↔❯↕❴✸❽ β➔✎❥☛❫❜❞✞❖➙❿✷❳✱❚✵➇✼❞❬rs❙❇❫❜❚✞❩
β⑩ ✉ ❭➛❽❊❞❋❣✞❚✵❿✷◆✆❖✑❣✞❤✆♦✠❖❇❙❇❫❜❚✞❩➜❭✤⑥✄❤➝❽
❣✦❤P♦✠❖❇❙✹❫❜❚➋❞✞❣❋❚✵❿➎◆P❖❱❿✷❳✱❞✕❫✠♣✱➔❷❚✦❳✱❞❼♣✛❚✞❩③⑥✸❤✆❭✤❴♠❽➞❪✆♦✼➉❜❞✞r❅❙❇❫❜❚✞❩➞✐❧❭➛❽✄❚✞❫✚➐❜❚✕➉✠❤❜❞✞❖❇❙❇❫❜❩➞✈ ✉ q❃❽✄r❾❥➟♦✆➉✆❙❇♦✠❙❉❪♠❳✱❚❋❣✞❚✦➉✚❿❷♦✆❳❸❩
❢✰➠③✇➡❽✆❫✆❚✵❥❜❳✛♦✼➐✆❙❇❫✆❙❇❫❜❩
✉
q❅❽
✉
qs➢✌❳✛❚✞❣✞❚✦➉✚❿▲♦✼❳✱❩
✉
qs➢✹✇➡❽✚➉✆❳✛❚✦➔✮❳✱♦✆❫❼❿❷❞✞❖❇❩✚❯✳⑩➋❽❜♣➎❥❜➣✏♣➎❿❷❞✕❫✆❣✞❚❱❯❀❩✏▼P❯❀❩
HAL author manuscript inserm-00165788, version 1
HAL author manuscript
✂✁☎✄
✁✝✆
✟✞
✁
❴↕❤✆❚■❿❷❞✞❣✦❤✚◆P➐✠❙❇❫❜❙✹❫ ❫✆❚✵❥❜❳✱♦✆➐❜❙✹❫✆❙❇❫ ❳✛❚✞❣✞❚✦➉✚❿❷♦✚❳✬♣s➄
✉
qs➢✹✇✤♣❷➅❍❳✱❚✦⑧✚❥☛❖❇❞✵❿❷❙❇♦✆❫✰♦✼➔❑❞✞❣✞❚✵❿✷◆✆❖✑❣✞❤✆♦✠❖❇❙❇❫❜❚❁❳✱❚✞❖✑❚✞❞✚♣✱❚➋❞✞❫✆❪➓❙➙❿★♣
❙❇❫❼❿❷❚✦❳✛❞✞❣✵❿❷❙❇♦✼❫✡✠❅❙→❿❸❤❊❿✷❤✆❚✤❚✞❫✚➐❜❚✦➉❜❤✆❞✞❖✑❙✹❫☞☛✷r❊❥✧♦✼➉❜❙❇♦✠❙❇❪❅❳✱❚✞❣✞❚✕➉✚❿❷♦✚❳➏♣✻➄▲❢♠➠❶✇✤♣❸➅↕❿✷❳✱❞✦❫❜♣✱r❍❙✮♣✯♣✱❙❇♦✠❫✡✠❑❞✚♣✸❙❇❫✚◗☛❚❼♣➎❿❷❙❘⑧❜❞✵❿❷❚❋❪❍❙✎❫
❿✷❤✆❚✤❖✹❙❇r❊➣☛❙✎❣✌☛✮➉✆❳✱❚✞➔✷❳✱♦✼❫✥❿❷❞✞❖✼❿❷❚✦❳❷❳❸❙➙❿✷♦✆❳➎◆s♦✆➔✳❿✷❤P❚❾❪✆♦✆❳✬♣✛❞❬❖✏♣➎❿✷❳✱❙❇❞✯❿✮❥❜r➝➂❼②➝♣✱❙❇❫✆⑧➝❪✆♦✚❥✆➣❜❖❇❚❾❙✑r❍r❊❥☛❫✆♦✆❤✆❙▲♣✷❿❷♦✠❣✕❤✆❚✞r❅❙▲♣✷❿✷❳❸◆✆❩✍✠❅❚
➔❸❙❘❳✯♣✷❿✄♣❸❤✆♦☞✠❑❚✞❪➜❿✷❤✆❞✵❿✻❙❇❫➜❿✷❤✆❙✮♣✸❿❷❚✦❳❸❳❷❙➙❿❷♦✚❳➎◆P❩✏❣❬❤P♦✠❖❇❙❇❫❜❚✦❳❸⑧❜❙✎❣❊❙❇❫❼❿❷❚✕❳➏❫P❚✵❥❜❳✱♦✆❫✠♣ ❣✞♦✆❫❼❿❷❞✞❙❇❫➜❿❷❞❋❣✦❤✚◆✆➐❜❙❇❫✠❙❇❫ ✉ qs➢✹✇❧♣✄❞✞❫✆❪✭❣✞♦❜❡
❚✵➇P➉✆❳✱❚❼♣✯♣ ❢♠➠❶✇✤♣✰❙❇❫ ❿✷❤✆❚ ❖✑❞✚♣➎❿➋➉❜❞✕❳▲❿↔♦✆➔■❿✷❤P❚ ❖✹❙❇⑧❜❤❼❿➋➉❜❚✞❳✱❙❇♦❜❪ ➄❸❞✦➔✎❿❷❚✕❳❸❫✆♦❜♦✼❫➁➅✯➂ t ❫ ♣✱❖❇❙✎❣✥❚❼♣ ♦✠➔■❿✷❤P❚ ♣➎❿✷❳❸❙✑❞✵❿❷❞✞❖
❖✎❙✑r❊➣✌❙✑❣✎☛➉✆❳✱❚✞➔✮❳✱♦✼❫✥❿❷❞✞❖➞❿❷❚✕❳❸❳❸❙➙❿❷♦✚❳➎◆P❩③➔✷♦✠❖❇❖❇♦☞✠❅❙❇❫✆⑧➟♣➎❥❜➉✆➉✆❳✱❚❼♣✯♣✱❙❉♦✼❫ ♦✼➔❵❿✷❤✆❚➋❪✆♦✆➉❜❞✦r❅❙❇❫❜❚✦❳❸⑧❜❙✎❣➋❙❇❫✆❤✆❙❉➣☛❙➙❿❷♦✆❳➎◆✰❣❋♦✼❫✥❿✷❳✱♦✼❖ ♦✠➔
❞✞❣✞❚✯❿✮◆✆❖✑❣✞❤✆♦✠❖❇❙❇❫❜❚❍❳✱❚✞❖✑❚✞❞❼♣✱❚❋❩↕❞✦➉✆➉✠❖✑❙✑❣❼❞✯❿✷❙❇♦✼❫ ♦✼➔✸❿✷❤✆❚❊❿❷❞✞❣✦❤✚◆P➐✠❙❇❫❜❙✎❫ ✉ qs➢✹✇ ❞❬❫✥❿❷❞✦⑧❜♦✆❫✆❙✎♣➎❿❷❩✸▼✏▼✚✇ ❺ ➆ ➀✆④✆➀✆➀✆❩➊r❅❞✕❳❸➐❜❚✞❪✆❖✹◆
❳✱❚✞❪❼❥☛❣❋❚✞❪ ❿✷❤P❚
✉
❢↔✐❊❭✤❡❸❙❇❫❜❪❼❥☛❣✞❚✞❪✰❞✞❣✥❚✵❿✷◆✆❖✑❣✞❤✆♦✆❖✹❙❇❫❜❚❁❳✱❚✞❖✑❚✞❞✚♣★❚✿❙❇❫ ❿✷❤✆❚➋r❅♦✆❳❸❫✆❙❇❫✆⑧♠➣➁❥✆❿❊❫P♦P❿❧❙❘❫ ❿✷❤✆❚➋❞✞➔✎❿❷❚✦❳❸❫P♦✠♦✆❫
✠❧❤✆❚✞❫❁❿✷❤✆❚✭❚❬❫➁➐❜❚✦➉❜❤✆❞✞❖✎❙❇❫☞☛✎❢♠➠ ✇ ❳✱❚✕⑧✚❥✌❖❇❞✯❿❸❙❇♦✆❫ ❙✮♣❧♦✆➉❜❚✦❳✱❞✬❿✷❙❇♦✼❫P❞✞❖➎➂ t ❫❁❿✷❤✆❚✭❞❬➔✎❿❷❚✕❳❸❫✆♦✆♦✆❫✆❩✪❿✷❤✆❚ ✉ qs➢❇✇ ❞✞❫❼❿❷❞✦⑧❜♦✆❫✆❙✎♣➎❿
❳✱❚❼♣❷➉❜♦✼❫❜♣✱❚❾❳✛❚✑✏❼❥✌❙❇❳✱❚❋❪➜❿✷❤✆❚❍♣➎❥❜➉✆➉✆❳✱❚✥♣✯♣✱❙❇♦✠❫➝♦❜➔✪❿✷❤✆❚❅❚✞❫✚➐❜❚✦➉❜❤✆❞✞❖✎❙❇❫☞☛✑❢✰➠ ✇ ❙✹❫✆❤❜❙❘➣✌❙→❿❷♦✼❳➎◆✧❣✞♦✆❫❼❿✷❳❷♦✼❖✽♦✆➔✸❞✞❣❋❚✵❿➎◆P❖✑❣❬❤P♦✠❖❇❙❇❫✌❚
❳✱❚✞❖❇❚✞❞✚♣✛❚➜➣✆◆
β➔✎❥☛❫✆❞✞❖➙❿✷❳✱❚✦➇✼❞❬rs❙❇❫❜❚✚➂✪❴↕❤✆❚❍➉✆❤P❞✦❳✱rs❞✞❣✞♦✠❖❇♦✆⑧❜❙❇❣✞❞✞❖✸➉✆❳❷♦✼➔✷❙✎❖✑❚➝♦✆➔➞❿✷❤P❚➜❿❷❞✞❣✦❤✚◆➁➐❜❙✹❫❜❙❇❫ ✉ q ➢✇❃❳✱❚✦⑧✚❥☛❖❇❞✵❿❷❙❇♦✠❫
❿❷❚❼♣✮❿❷❚✞❪❍➣✆◆✭❞✦➉✆➉❜❖✎❙✑❣✞❞✯❿❸❙❇♦✆❫✭♦✠➔↕❿✷❤✆❚❊❳✱❚✞❣❋❚✦➉✚❿✷♦✆❳ ❞✦⑧✆♦✆❫✆❙✎♣➎❿✱♣ ➄✓✒✹❯✽❳❸♦✍✔✖✕✱♣➎❥✆➣✌♣✷❿❷❞✦❫✆❣✥❚❾❯❀❩✳❫P❚✵❥❜❳✱♦✆➐✆❙✹❫✆❙❇❫❁❭✤❩✏❫✆❚✵❥❜❳✛♦✼➉❜❚✦➉✚❿✷❙❉❪✠❚
q ❞✞❫✆❪✧♣✷❥✠➣☛♣➎❿❷❞✦❫❜❣❋❚❶❯❀➄❸④✆❡ ✆ ➅❷➅✸❞✦❫P❪❍❞✦❫✥❿❷❞✦⑧❜♦✆❫✆❙✎♣➎❿✱♣✻➄✬▼✏▼✚✇ ❺ ➆ ➀✆④✆➀✆➀✆❩✘✗❶✇ ❺❜➀✠❹ ⑤ ❩✘✗③✇✚✙✥❺❜❻✆❻ ➆ ❞✦❫P❪❑✇✄❯❀④✆⑤✠❹✍✙➁➀✚➅
❙❇❫❜❪✼❙✑❣✞❞✯❿❷❚✞❪➜❿✷❤✆❞✵❿✽❿✷❤✆❚➜♣✷❥✆➣✚❿✷◆➁➉✌❚❊♦✆➔✪❿❷❞✞❣✦❤✚◆P➐✠❙❇❫❜❙❇❫
✉
qs➢✹✇➛❙✑r❍➉❜❖❇❙✎❣❋❞✵❿❷❚✞❪➝❞✦❳✱❚❵❿✷❤✆❚❾❫P❚✎✠
✉
qs➢✮❡➏♣✱❚✞❫✌♣✱❙➙❿❷❙❘◗☛❚❾❳✱❚✞❣❋❚✦➉✚❿❷♦✚❳
➣❜❙❇❫❜❪✼❙❇❫✆⑧➝♣✱❙➙❿❷❚✚➂
❴↕❤✆❚✦❳✱❚✞➔✷♦✆❳✱❚✞❩❵❙❇❫➓❿✷❤✆❚⑨❖❇❙✎r❊➣✌❙✑❣✎☛➉✆❳✱❚✞➔✮❳✱♦✆❫❼❿❷❞✞❖③❿❷❚✦❳❸❳❸❙→❿❷♦✚❳➎◆➟♦❜➔❑❿ ❤✆❚⑨❪✆♦✆❳✬♣✱❞✞❖❊♣✷❿✷❳❸❙✑❞✵❿✮❥❜r❅❩✤❚❬❫P❪✆♦✼⑧❜❚✕❫✆♦✚❥✏♣❍❿❷❞✞❣✦❤✚◆➁➐❜❙✹❫❜❙✎❫
➔❷❞✞❣✞❙✎❖✎❙→❿❷❞✵❿❷❚❼♣➡❞✞❣✞❚✯❿✮◆✆❖✑❣✞❤✆♦✠❖❇❙❇❫❜❚ ❳✱❚✞❖✎❚❋❞P♣✛❚ ◗❜❙✑❞ ❞ ❿❷❞✞❣✦❤✚◆➁➐✠❙❇❫❜❙✎❫ ✉ qs➢❇✇ ♣➎❥❜➣✚❿✷◆➁➉❜❚✚➂ t ❫ ❿✷❤✆❚ ❞✞➔✎❿❷❚✦❳❸❫✆♦❜♦✆❫✆❩■❿✷❤✆❚
❿❷❞✞❣✦❤✚◆➁➐❜❙❇❫✠❙❇❫☞☛✉ qs➢✹✇ ❞❬❫P❪ ❿✷❤P❚ ❚✞❫✚➐☛❚✦➉❜❤✆❞✞❖✎❙❇❫✛☛✮❢✰➠③✇ ❿✷❳✛❞✦❫✠♣✱r❅❙✮♣✯♣✱❙❇♦✠❫❜♣➟❙✹❫✥❿❷❚✦❳✱❞✞❣✯❿ ❿✷♦ ❣✕♦✆❫❼❿✷❳❷♦✼❖➌❣✞❤✆♦✠❖❇❙❇❫❜❚✦❳❸⑧❜❙✮❣
❿✷❳✱❞✦❫❜♣✱r❅❙▲♣✯♣✱❙❉♦✠❫✌➂
q❧❚✦◆✡✠❑♦✼❳✱❪✠♣ ➃✚❴❛❞✞❣✦❤✚◆✆➐❜❙❇❫✆❙❇❫
✉
qs➢✌❳✱❚✞❣✞❚✦➉✚❿▲♦✼❳✸♣✷❥✆➣✚❿✮◆➁➉❜❚✚♣✱❩✚❢ ❥❏♦✆➉✆❙❇♦✼❙❉❪❑❳✛❚✞❣✞❚✦➉✚❿❷♦✆❳❸❩❜❞✞❣✞❚✬❿✮◆✆❖✑❣✞❤✆♦❜❖✹❙❇❫❜❚✞❩✚❿❷❞✞❣✦❤✚◆P➐✠❙❇❫✆❙❇❫☛❩
♣➎❿✷❳❷❙❇❞✵❿✮❥☛r
✇✄❥❜❫✆❫✆❙❇❫✆⑧❑❿✷❙→❿❸❖❇❚ ➃ ✉ qs➢✜☛✑❢✰➠ ✇ ❳✱❚✞❣✞❚✕➉✚❿✷♦✆❳✬♣↕❙❇❫❼❿❷❚✦❳✛❞✞❣✵❿✷❙❇♦✆❫❅❞✦❫P❪➜❭✤⑥❱❤❧❳✱❚✞❖❇❚✥❞❼♣✱❚
HAL author manuscript inserm-00165788, version 1
✂✁❧✁✝✆☎✄✝✆✟✞
✞
✁✠✡✄✝✁
❴↕❤✆❚ ♣➎❿✷❳❸❙❉❞✵❿✮❥✌r ❙✮♣↔❞➟❣✞♦✆r❊➉❜♦✼❫❜❚✞❫✥❿➌♦✼➔✭r❊❥✌❖➙❿❷❙❘➉❜❖✑❚✓❣❋♦✼❳✮❿✷❙✑❣❼♦❜❡▲➣✼❞❼♣✱❞✞❖❅⑧❜❞✞❫✚⑧❜❖✎❙✑❞✢❖❇♦✠♦✆➉ ❣✞❙❘❳✱❣✵❥☛❙➙❿★♣■❿✷❤P❞✵❿➌❣✞♦✆❫❼❿✷❳❷♦✼❖
r❅♦✼◗✼❚✞r❍❚✞❫✥❿❛❞❼♣ ✠❅❚✞❖✎❖●❞P♣✻❣✞♦✆⑧✆❫✆❙➙❿❷❙❘◗☛❚✞❩✌r❅♦P❿❷❙❘◗❜❞✵❿❷❙❇♦✆❫✆❞✞❖✏❞✞❫✆❪✭❚✞r❅♦✚❿✷❙❇♦✼❫P❞✞❖✪❞✥♣❸➉❜❚✞❣✵❿✱♣✻♦✠➔✪➣✼❚✞❤❜❞❋◗❜❙❉♦✼❳✯➂ t ❫❊❿✷❤✆❚✤❪✆♦✼❳✬♣✛❞❼❖
♣➎❿✷❳❷❙❇❞✵❿✮❥☛r❅❩■❙❇❫ ❞✞❪✆❪✆❙➙❿❷❙❇♦✼❫ ❿✷♦ ➔✎❥☛❫✆❣✯❿❸❙❇♦✆❫✆❞✞❖❍❿❷❚✦❳❷❳❸❙➙❿❷♦✆❳❸❙❇❚✚♣✰❪✆❚✞➔➎❙❇❫❜❚✞❪ ➣✆◆ ❿✷❤P❚✞❙✹❳✢♣❷➉❜❚✞❣✞❙❇➔❸❙✑❣➛❣✞♦✼❳✷❿✷❙❇❣✞❞✞❖❁❞✞➔✷➔❸❚✕❳✱❚✞❫❼❿✱♣
➄▲➍❶❚✦❳✱❚✕❫✆❪✠♣★❚☞☛✍✌✏✎✒✑✔✓ ✖✕✗✕ ❺✏❽✥✐❅❚✞❫✆❙✑❞✵❥✭❞✞❫P❪➜❴↕❤✆❙✑❚✦❳❸❳❸◆ ✖✕✗✕ ⑤✚➅✱❩✚❿✠❑♦➜r❑❞❬❙❇❫❏❣✞♦✠r❊➉❜❞✦❳✷❿✷r❅❚✞❫❼❿✱♣✱❩✚❿✷❤✆❚❾♣✷❿✷❳✱❙❇♦●♣✛♦✼r❑❚P♣➊❞❬❫❜❪
❿✷❤✆❚❍r❑❞✵❿✷❳❸❙❘➇❜❩↕❞✦❳✛❚❍❪✆❙✎♣➎❿❷❙❇❫✚⑧✚❥☛❙▲♣✱❤❜❚❋❪❁➄✖✗❵❳✱❞✦◆✚➣❜❙✑❚✞❖ ✖✕✗✕ ➀✌❽✌✐❅❚✚♣❸➣❜❞✞❫✘☛✍✌✙✎✒✑✚✓ ✖✕✗✕ ❻✠❽ ✗✤❚✦❳✱➔✷❚❬❫➌❞✞❫✆❪✜✛➟❙❇❖✮♣✱♦✠❫ ✖✕✗✕ ④✚➅✯➂
❴↕❤✆❚ ♣✱❚✞❫✠♣✛♦✼❳✱❙❇r❅♦✚❿✷♦✆❳✧❿❷❚✕❳❸❳❸❙➙❿❷♦✚❳➎◆ ✠❅❤✆❙✑❣✞❤➛r❍❞✞❙❇❫❜❖✹◆ ❣❋♦✼❫✌♣✱❙✮♣❸❿✱♣➋♦✆➔✭r❍❞✯❿✷❳❸❙❘➇➛➣☛❚❬❖❉♦✠❫✚⑧✌♣✭❿❷♦✓❿✷❤✆❚✓♣★❚✞❫✠♣✛♦✼❳✱❙❇r❅♦✚❿✷♦✆❳
❣✞♦✆❳▲❿✷❙❉❣✞♦✠❡✮➣❜❞❼♣✛❞❬❖s⑧❜❞✞❫✚⑧❜❖✎❙✑❞➟❣❬❙❳✱❣✵❥☛❙➙❿✬♣ ➂❊❴↕❤✆❚➟❖✹❙✑r❊➣✌❙✑❣✎☛➉✆❳✱❚✞➔✮❳✱♦✼❫✥❿❷❞✞❖❍➄✮❯✳⑩●➅ ❿❷❚✕❳➎❳❸❙→❿❷♦✼❳➎◆ ❚✞❫✚❳✱❙❇❣✞❤❜❚✞❪ ❙❇❫ ♣➎❿✷❳❷❙❇♦●♣✛♦✠r❅❚✚♣
➣❜❚✞❖❇♦❜❫✚⑧✏♣➊❿▲♦❑❿✷❤P❚❾➔✮❳✱♦✆❫❼❿❷❞✦❖☛❣✞♦✆❳➎❿✷❙❇❣✞♦❜❡▲➣❜❞✥♣★❞❬❖❜⑧❜❞✞❫✚⑧❜❖✎❙✑❞✤❣❬❙❇❳✱❣✯❥✌❙➙❿★♣✯➂✥✐❊◆❜♣✱➔▲❥☛❫✆❣✵❿❷❙❇♦✆❫❍❙❇❫➜❿✷❤P❚❼♣✱❚✤❖✎❞✯❿✮❿❷❚✦❳✸❣✕❙❘❳✱❣✵❥☛❙➙❿✱♣✻❣✞❞✵❥✽♣✱❚✚♣
❣✞♦✆⑧✆❫✆❙➙❿❷❙❉◗✼❚ ❪✼❙✮♣✱♦✆❳✱❪✆❚✦❳★♣➛♣➎❥☛❣✦❤ ❞✚♣➡♦✚➣✌♣✱❚✕❳✛◗✼❚✞❪ ❙❇❫ ♦✚➣✌♣★❚❼♣✯♣✱❙❘◗☛❚✞❡❸❣❋♦✼r❊➉✚❥☛❖✮♣✱❙❘◗☛❚ ❪✆❙✮♣✱♦✆❳✱❪✆❚✦❳➡➄▲➍ ❳✱❞✞❪✠♣❷❤✆❞✎✠ ❞❬❫❜❪
▼✆❤✆❚✦➉✆➉❜❞✕❳✱❪✧❺❜➀✆➀✆➀✌❽ ✗❵❳✱❞✦◆✚➣❜❙✑❚✞❖❛❞❬❫P❪✧✇❶❞✵❥☛❣✞❤➝❺❜➀✆➀✆➀●❽✽⑥✄❞✦❳✱❖✮♣✯♣★♦✆❫➝❺❜➀✆➀ ➅✱❩●❯❀❞✦❳❸➐✆❙❇❫✌♣✛♦✼❫✣✢➎♣ ❪✼❙✮♣★❚✞❞✥♣★❚➜➄✮✐❾❥❜➣❜♦✠❙✑♣❵❞✞❫✆❪
❯↕❙❇❖❇❖❇♦✠❫
✖✕✗✕
⑤✚➅❛❞✦❫✆❪❅❣✞♦❜❣✞❞✞❙❇❫✆❚❱❥✏♣★❚✦❳✬♣➊➄✥✤❊♦✆❖❘➐❜♦☞✠✦☛✍✌✗✎✒✑✧✓❜❺❜➀✆➀
➆ ➅ ➂
⑥✸❤✆♦✠❖❇❙❇❫❜❚✦❳❸⑧❜❙✑❣ ❙❇❫❼❿❷❚✕❳➏❫P❚✵❥❜❳✱♦✆❫✆❚❼♣ ❞✦❳✱❚ ❪✆❙✮♣➎❿✷❳✱❙❘➣✚❥✆❿❷❚✞❪ ❿✷❤✚❳❷♦P❥P⑧✆❤✆♦✚❥✆❿⑨❿✷❤✆❚ ♣➎❿✷❳❷❙❇❞✵❿✮❥☛r ❞✞❫✆❪ ❿✷❤✆❚✞❙❘❳ ❪✆❚❬❫❜♣★❚ ❞❬❫❜❪
✠❅❙❇❪✆❚✚♣❷➉✆❳✱❚✞❞✞❪ ❖❇♦❜❣✞❞✞❖❅❞✦➇❜♦✆❫➡❣✞♦✠❖❇❖✑❞✵❿❷❚✦❳✱❞✞❖❊❫❜❚✯❿ ✠❅♦✚❳❸➐➡❙✮♣❁❖✑❞✦❳❸⑧❜❚✞❖❘◆➡❳✱❚❼♣➎❿✷❳✱❙❇❣✯❿❷❚✞❪ ❿▲♦ ❿✷❤✆❚✰r❍❞✯❿✷❳❸❙❘➇➛❣❋♦✠r❊➉❜❞✦❳➎❿❷r❅❚✞❫❼❿
✠❧❤✆❚✦❳✱❚ ❙→❿❅➉✆❳✱❙✎rs❞✦❳✱❙❇❖✹◆✰❿❷❞✦❳❸⑧❜❚✵❿✱♣❊❿✷❤P❚♠♣➎❿✷❳✱❙❇❞✯❿❷❞❬❖❶♦P❥✆❿✷➉✚❥➁❿❅❫✆❚✯❥❜❳✱♦✼❫P❚❼♣❏➄ t ❨✞❨✥♦➟❞✦❫P❪♠➍❶♦✠❖❇❞✞r ✖✕ ✙✍✙❜❽❱q❧❞✎✠❑❞✦⑧✚❥●❣✞❤✠❙
✖✕✗✕ ❺✌❽✏❴❛❚✦➉✆➉❜❚✦❳ ❞✦❫P❪❏➍❶♦✠❖❉❞❬r ❺❜➀✆➀ ➆ ❽★✛➟❞✞❫➁⑧✜☛✍✌✩✎✒✑✔✓✪❺❜➀✆➀✆④✚➅★➂✌❴↕❤✆❚✦◆✭❞✕❳✱❚❾❿✷♦✆❫✆❙❇❣✞❞✞❖✎❖❇◆➌❞✞❣✵❿❷❙❉◗✼❚❅❞❬❫P❪■❙❇❫✚◗❜♦✠❖❘◗✼❚✞❪❁❙✎❫
❳✱❚✎✠❑❞✦❳✱❪➝❳✱❚✞❖❇❞✵❿❷❚❋❪✧➉✆❳✱♦❜❣✞❚✞❪❼❥❜❳✛❞✦❖✪❖✑❚✞❞✦❳✱❫✆❙❇❫✆⑧➌❞❬❫P❪ ✠❑♦✆❳❸➐✠❙❇❫➁⑧❁rs❚❬r❑♦✼❳❸◆➌➄✖✗❵❳✱❞✦◆✚➣❜❙✑❚✞❖✪☛✍✌✩✎✒✑✚✓
✖✕✗✕✚➆
❽✏❭✤♦●♣✛❞✦➐❜❙✙☛✍✌✩✎✒✑✔✓
✖✕✗✕✚➆ ❽❊❭❵➉❜❙✑❣✞❚✞❖✎❖✑❞➓❺❜➀✆➀✚❺✆➅✯➂✤⑥✸❤✆♦❜❖✹❙❇❫❜❚✦❳❷⑧✠❙✑❣✢❙❇❫❼❿❷❚✦❳❸❫P❚✵❥❜❳✱♦✆❫✆❚❼♣↔❞✕❳✱❚➓❙❇❫✆❫❜❚✦❳➎◗✼❞✵❿❷❚✞❪ ❫✆♦✚❿✭♦✆❫✆❖❘◆ ➣✆◆ ❣✞♦✼❳✷❿✷❙❇❣✞❞✞❖s❞❬❫❜❪
❿✷❤✆❞✞❖❇❞✞rs❙✎❣ ⑧❜❖➙❥✆❿❷❞✞r❍❞✯❿❷❚✦❳❸⑧✆❙❇❣ ❙❇❫✆➉✚❥✆❿✱♣➛➣✚❥✆❿ ❞✞❖✎♣✛♦ ➣✆◆ ❫✆❙✑⑧✆❳✱❞✞❖✰❪✆♦✼➉❜❞✞r❅❙❇❫❜❚✦❳❸⑧❜❙✑❣ ❫❜❚✵❥❜❳✛♦✼❫P❚❼♣❃❞❬❫P❪ ➉❜❚✦➉✚❿❸❙❉❪✠❚
❣✞♦✆❫❼❿❷❞✦❙❇❫✆❙❇❫✆⑧❊❿❷❚✦❳❸r❅❙❇❫❜❞✞❖▲♣➊♦✼❳✱❙❘⑧❜❙❇❫❜❞✵❿❸❙❇❫➁⑧❍➔✮❳✱♦✠r➛❳✛❚✞❣✵❥❜❳❸❳✱❚✕❫❼❿❀❣✦♦✆❖❇❖✑❞✵❿❷❚✦❳✱❞✞❖✎♣❛♦❜➔➊♣✷❿✷❳❸❙❇❞✵❿❷❞✞❖❜❚✞➔✷➔❸❚✦❳✛❚❬❫✥❿✽❫✆❚✵❥❜❳✱♦✆❫✆❚✥♣❛➄▲➍❶♦✠❖❇❞✥r
❞✦❫P❪✿➍❵❚✞❫✆❫❜❚✵❿✑❿ ✖✕✗✕ ❹✥➅✬➂ t ❫P❪✆❚✞❚✞❪✆❩➊❿✷❤P❚■❫✆❚✯❥❜❳✱♦✼➉❜❚✕➉✚❿✷❙❇❪✆❚❼♣✱❩✄♦✚➉❜❙❇♦✠❙❇❪✠♣❑➄❸❚✞❫✚➐❜❚✦➉❜❤✆❞✞❖✑❙✹❫✌♣❑➄▲✈ ✉ q✤➅❅❞✞❫P❪⑨❪P◆P❫✆♦✆❳❸➉✆❤✆❙❇❫✠➅
❞✦❫P❪❏❿❷❞✞❣✕❤✚◆✆➐❜❙✹❫❜❙❇❫✌♣ ➄➏♣➎❥❜➣✌♣✷❿❷❞✦❫✆❣✥❚ ❯ ➄✬▼✚❯✽➅✱❩✌❫✆❚✯❥❜❳✱♦✼➐❜❙❇❫✆❙❇❫❜❚❊➄
✉
q✤➅✄❭❃❞❬❫P❪
✉
q❵➍③➅✛❩✳❞✕❳✱❚❊❖❇♦✠❣❋❞❬❖✑❖✹◆❏❳✬❚✞❖✑❚✞❞❼♣✛❚✞❪■➔✮❳✱♦✌r
❿✷❤✆❚❁❳✱❚❋❣✵❥❜❳❸❳✱❚✦❫✥❿❅❣✕♦✆❖✹❖✑❞✵❿❷❚✕❳✱❞✞❖✎♣s♦✼➔❵❿✷❤✆❚➋♦✚❥✆❿✷➉✚❥✚❿✤❫P❚✵❥❜❳✱♦✆❫✆❚❼♣s❞✦❫P❪♠➉❜❞✕❳➎❿✷❙✑❣❬❙➉✌❞✵❿❷❚❁❙❇❫ ❿✷❤✆❚❁❳✱❚✕⑧✚❥✌❖❇❞✯❿❸❙❇♦✆❫✰♦✆➔❍♣➎❿✷❳❸❙❉❞✵❿❷❞❼❖
❣✦❤P♦✠❖❇❙✹❫❜❚✕❳❸⑧✠❙✑❣❾❿✷❳✱❞✦❫❜♣✱r❍❙✮♣✯♣✱❙❇♦✠❫✭➄✮♥✻❚❬❫P❪P◗✼❞✞❙✙☛✍✌✩✎✒✑✔✓
✖✕✗✕
❻✌❽✏❭❾❫❜❪✆❚✦❳★♣✱♦✆❫✫☛✍✌✩✎✒✑✚✓
✖✕✗✕✚➆
❽✏❭✤♦●♣✛❞✦➐✠❙❀❞✞❫✆❪✧q❧❞✎✠❑❞✦⑧✚❥●❣✞❤✠❙
HAL author manuscript inserm-00165788, version 1
❿✷❤✆❚ ♣✛❚✞❫✠♣✱♦✆❳✱❙❇r❅♦P❿▲♦✼❳➟❿❷❚✦❳✷❳❸❙➙❿❷♦✆❳➎◆ ♦✆➔✢❿✷❤✆❚ ❪✆♦✆❳✬♣✱❞✞❖➟♣➎❿✷❳❸❙❉❞✵❿✮❥✌r ✠❑❤✆❚✦❳✱❚ ❿✷❤P❚ ❳✱❚✦⑧✚❥☛❖✑❞✵❿❸❙❉♦✼❫ ♦✆➔➡❣✞❤✆♦✠❖❇❙❇❫❜❚✦❳❸⑧❜❙✮❣
❿✷❳✱❞✦❫❜♣✱r❅❙▲♣✯♣✱❙❉♦✠❫✧➣✆◆s❿❷❞✞❣✞❤✚◆✆➐❜❙❇❫✆❙✹❫➌❤✆❞✚♣❱➣✼❚✞❚✞❫■rs❞✞❙❇❫✠❖❇◆➋♣➎❿✮❥☛❪✆❙✑❚✞❪✆❩➊♣✷❿✷❙✹r❊❥☛❖✑❞✵❿✷❙❇♦✆❫✭♦✠➔➊❿✷❤P❚❾❿❷❞✞❣✦❤✚◆✆➐❜❙❇❫✠❙❇❫
✉
qs➢✮❩
✉
q✁
❞✦❫P❪ ✉ q✁✂⑨❳✱❚❋❣✞❚✦➉✚❿❷♦✚❳✬♣ ➣✆◆ ❚❬❫P❪✆♦✼⑧❜❚✕❫✆♦✚❥✏♣✱❖✹◆ ❳✱❚✞❖✑❚✞❞✚♣✱❚❋❪❃❿❷❞❋❣✦❤✚◆✆➐❜❙❇❫✠❙❇❫✌♣✢➔❷❞✞❣✞❙✎❖✑❙➙❿❷❞✵❿❷❚❼♣↔❿✷❤✆❚ ✉ ❢ ✐❅❭✤❡❸❚✦◗✼♦✼➐❜❚✞❪
❳✱❚✞❖❇❚✞❞✚♣✛❚ ♦✠➔❅❭❧⑥❱❤✌➂①✐✤❥☛❚ ❿❷♦➓❿✷❤P❚✿➉❜♦❼❿❷❚✦❫✥❿s❪✆♦✼➉❜❞✕r➜❙❇❫❜❚↔➄❷✐❧❭❵➅☛✑✐❊❺➟❙❇❫✆❤✠❙❘➣☛❙➙❿❷♦✆❳➎◆➟❣❋♦✼❫✥❿✷❳✱♦✼❖❶♦✠➔❅❞✞❣✥❚✵❿✮◆P❖✑❣❬❤P♦✠❖❇❙❇❫✌❚
➄➎❭✤⑥✄❤✚➅❛❳✱❚✞❖✎❚❋❞❼♣★❚✞❩✼❿✷❤P❚❼♣✱❚③❿❷❞✞❣✦❤✚◆P➐✠❙❇❫❜❙✹❫s❳✱❚✦⑧✚❥☛❖✑❞✵❿❸❙❉♦✼❫✌♣❛❳✱❚✑✏❼❥☛❙❘❳★❚❊♣➎❥❜➉✆➉✆❳✱❚❼♣✯♣✱❙❉♦✼❫❏♦✼➔❀❪✆♦✼➉❜❞✞r❅❙❇❫❜❚✦❳❸⑧❜❙✎❣③❿✷❳✱❞✦❫✌♣✱r❅❙✮♣✯♣✱❙❇♦✌❫
➄➎❭✤❫✆❪✆❚✦❳★♣✱♦✆❫☎☛✍✌ ✎✒✑✚✓ ✖✕✗✕✚➆ ❽✌▼✚❿❷❚✞❙❇❫✚➣❜❚✦❳❷⑧ ☛ ✌✏✎✒✑✚✓ ✖✕✗✕ ✙✠❽➁q❧❚❬r❏❚✞❖✗☛✍✌ ✎✒✑✚✓❜❺❜➀✆➀✚❺✆➅✯➂✚⑥✄♦✆❫✠♣✱❙✮♣➎❿❷❚✕❫❼❿ ✠❅❙➙❿✷❤❾❿✷❤P❚③➉✆❳✱❚✚♣✱❚✞❫✆❣✥❚
♦✆➔✳❿❷❞✞❣✦❤✚◆P➐✠❙❇❫✆❙❇❫
✉
qs➢✳❳✱❚❋❣✞❚✦➉✚❿❷♦✚❳✬♣✻➄
✉
qs➢✹✇✤♣❸➅✸❙❇❫s❣✞❤✆♦✠❖❇❙❇❫❜❚✦❳❸⑧❜❙✑❣❾❙❇❫❼❿❷❚✦❳❷❫✆❚✵❥❜❳✱♦✆❫✠♣✻➄✖✗✤❚✦❳✱➔✷❚✞❫
✖✕✗✕✪
❽✼q❧❞✞❫P❚✦➐❜♦ ☛✍✌ ✎✒✑✚✓
✖✕✗✕ ❻✚➅✱❩✪❿✷❤✆❚❍❿❷❞✞❣✦❤✚◆➁➐❜❙✹❫❜❙❇❫☞☛✉ qs➢ ➔❸❞✞❣✞❙✑❖✹❙→❿✱❞✵❿✷❙❉♦✼❫↔♦✠➔❵❭✤⑥✄❤✿❳✛❚❬❖ ❚✞❞❼♣✛❚■❙✮♣❊❪✆❙❇❳✱❚✞❣✵❿ ✠❊❤P❚✦❳✱❚✞❞✚♣❵❿✷❤✆❚❍❿❷❞✞❣✦❤✚◆P➐✠❙❇❫❜❙❇❫☞☛✉ q✁
❞✦❫P❪
✉
q✁✂✻❳✱❚✦⑧✚❥☛❖✎❞✯❿❸❙❇♦✆❫✠♣ ❞✕❳✱❚❊❙✹❫❜❪✆❙❘❳★❚✞❣✵❿✻❞✕❫✆❪➝❳✱❚✑✏❼❥☛❙❘❳✱❚➜❫✆❙→❿✷❳➏❙✑❣❊♦✚➇❜❙✑❪✆❚❊➄✬▼✚❿❷❚✞❙❇❫✚➣❜❚✦❳❸⑧✫☛ ✌ ✎✒✑✚✓
✖✕✗✕
✙❜❽✌q❧❚✞r❍❚✞❖ ☛✍✌✩✎✒✑✔✓
❺❜➀✆➀✚❺✆➅✯➂❵❴↕❤✚❳✛❚✞❚ ♣✷❥✠➣➁❿➎◆➁➉❜❚✚♣➌♦✠➔➜❿❷❞❋❣✦❤✚◆✆➐❜❙❇❫✠❙❇❫ ✉ qs➢➜➣❜❙❇❫❜❪✆❙✎❫➁⑧ ♣✱❙➙❿❷❚❼♣➋❞✕❳✱❚♠➉✆❳✛❚P♣✛❚✞❫❼❿✭❙❇❫✢❿✷❤✆❚➓➣✆❳✱❞✞❙❇❫✌❽❧❣✞❖✎❞✚♣★♣✱❙✎❣❋❩
♣✱❚✕➉✚❿✷❙❇❪✠❚❋❡➏♣✱❚✞❫✠♣✱❙→❿❸❙❘◗☛❚❅❞✞❫✆❪■❫P❚✎✠ ✉ qs➢✮❡✱♣✱❚✞❫✌♣✱❙➙❿❷❙❉◗✼❚❅➄▲➍❶❚❼❞✯❥☎✄✱♦✚❥☛❞✦❫✫☛✍✌✩✎✒✑✔✓✪❺❜➀✆➀✆➀✚➅✯➂ t ❫❍❿✷❤P❚❍♣➎❿✷❳❸❙❇❞✯❿❷❞❬❖↕♣✛❚❬❫✌♣✛♦✼❳❷❙✹r❑♦P❿❷♦✆❳
❿❷❚✦❳✷❳❸❙➙❿❷♦✆❳➎◆P❩❱❿✷❤✆❚↔❪✼❙❇❳✱❚✞❣✯❿❊❿❷❞✞❣✦❤✚◆P➐✠❙❇❫✆❙❇❫☞☛
✉
qs➢❅❣❋♦✼❫✥❿✷❳❸♦✆❖✤♦✼➔s❭❊⑥✸❤✢❳✛❚❬❖✑❚✞❞✥♣★❚ ❙▲♣✭rs❚✞❪✆❙✑❞✵❿❷❚✞❪♠➣✆◆✰❿❸❤P❚ ❫✆❚ ✠ ✉ qs➢✮❡
♣✱❚✞❫❜♣✱❙➙❿❸❙❘◗☛❚❍♣➎❥❜➣✚❿✷◆➁➉❜❚❊♦✠➔ ✉ qs➢❇✇ ➣❜❙❇❫❜❪✼❙❇❫✆⑧➋♣✱❙➙❿❷❚❊➄➎q❧❚✞rs❚❬❖ ☛✍✌✩✎✒✑✔✓✏❺❜➀✆➀✆❻✚➅✯➂✚➍❵❚❋❣✞❞✵❥✏♣✱❚❧♦✼❫✆❖❇◆✭♦✆❫✆❚❾❿➎◆➁➉❜❚❊♦❜➔ ✉ qs➢✎✇
❤✆❞✚♣❵➣❜❚❋❚❬❫↔❣✞❤✆❞✕❳✱❞✞❣✵❿❷❚✦❳✱❙❘❨❬❚✞❪ ➣✆◆ r❅♦✠❖✑❚✞❣✵❥☛❖✑❞✦❳❾rs❚✞❞✞❫✌♣✛❩❀❿✷❤✆❙✮♣✤➉✆❤✆❞✦❳✱rs❞✞❣✞♦❜❖❇♦✼⑧❜❙❇❣✞❞✞❖✑❖✹◆↔❪❜❚✞➔➎❙❇❫❜❚✞❪ ❫P❚✎✠ ❿❷❞✞❣✕❤✚◆✆➐❜❙✹❫❜❙✎❫
❳✱❚✞❣❋❚✦➉✚❿✷♦✆❳ ➣❜❙❇❫✆❪✆❙❇❫✆⑧ ♣✱❙➙❿❷❚ ✠❅❤✆❙✑❣✞❤ ❣✞♦✚❥✌❖❉❪ ❣✞♦✆❳❸❳✱❚✥♣❸➉❜♦✆❫✆❪ ❿✷♦ ❞ ❪✚❙✮♣✷❿✷❙✹❫❜❣✯❿ ❳✱❚❋❣✞❚✦➉❼❿▲♦✼❳ r❅♦❜❖❇❚✞❣✵❥☛❖✑❚ ♦✆❳ ❞
❣✞♦✆❫✆➔✷♦✼❳❷r❍❞✯❿✷❙❇♦✼❫❜❞✞❖↕♣➎❿❷❞✯❿❷❚❾♦✆➔✪❿✷❤✆❚ ✉ qs➢✹✇ ➄✝✆❅♦✆❖✮♣➎❿ ☛✍✌★✎✒✑✚✓✏❺❜➀✚➀ ➅ ✠❅❞❼♣❛❿❷❚✦❳❸r❅❚❋❪✧❫P❚✎✠ ✉ qs➢✮❡➏♣✱❚✞❫✌♣✱❙➙❿❷❙❘◗☛❚❾❳✱❚✞❣❋❚✦➉✚❿❷♦✚❳
➣❜❙❇❫❜❪✼❙❇❫✆⑧➝♣✱❙➙❿❷❚✚➂
t ❫ ❿✷❤P❚✓❖✎❙✑r❊➣✌❙✑❣✎☛✑❯✳⑩ ❿❷❚✦❳❸❳❸❙→❿❷♦✼❳➎◆ ♦✼➔✭❿✷❤✆❚➟❪✆♦✼❳★♣✱❞✞❖■♣✷❿✷❳❸❙❇❞✵❿✮❥❜r❅❩➝❫✆♦❃❪✆❚✵❿❷❞✦❙❇❖✑❚✞❪ ❞✞❫✆❞✞❖✹◆☛♣✱❙✮♣⑨♦✆➔■❿✷❤✆❚➓❿❷❞✞❣✕❤✚◆✆➐❜❙✹❫☛❙✎❫
❳✱❚✦⑧✚❥☛❖❇❞✵❿❷❙❇♦✆❫❁♦✆➔✄❣✞❤✆♦✆❖❇❙❇❫❜❚✦❳❸⑧❜❙✎❣❊❿✷❳✱❞✦❫❜♣✱r❍❙✮♣✯♣✱❙❇♦✆❫✿♣✱❙✑r❍❙✎❖✑❞✦❳✄❿✷♦✧❿❤✆❞✵❿➞➉❜❚✦❳❸➔✷♦✆❳➏r❑❚✞❪❁❙✹❫➝❿✷❤✆❚➝♣✱❚✞❫✠♣✛♦✼❳✱❙❇r❅♦✚❿❷♦✚❳✸❿❷❚✦❳➎❳❷❙➙❿❷♦✼❳✷◆
❤✆❞✚♣✭◆❜❚✵❿s➣❜❚✞❚✞❫➡❪✆♦✼❫P❚✚➂❊▼❜❚✵◗☛❚✦❳✛❞❬❖❧♦✚➣✏♣✱❚✦❳❸◗❜❞✯❿✷❙❇♦✼❫✌♣➌❤✆♦☞✠❅❚✯◗☛❚✦❳■➉❜♦✆❙❇❫❼❿❅❿✷♦➛❞✿❿❷❚✕❳❸❳❸❙➙❿▲♦✼❳❸❙❉❞❬❖s♣❸➉☛❚✞❣✞❙✹➔❷❙✎❣✞❙➙❿✷◆➛❙❇❫➟❿✷❤✆❙➎♣
❳✱❚✦⑧✚❥☛❖❇❞✵❿❷❙❇♦✆❫✌➂ t ❫✆❪✆❚✞❚❋❪✆❩●❿✷❤✆❚❅❖❇❙✎r❊➣✌❙✑❣✎☛✑❯✏⑩✿❿❷❚✕❳❸❳❸❙➙❿❷♦✆❳➎◆✭❙✮♣ ❚✞❫✚❳✱❙✑❣❬❤P❚✞❪■❙❇❫➋♣➎❿✷❳❸❙❇♦✌♣✱♦❜r❅❚❼♣ ❞✞❫✆❪✭❞➜❤✆❙❇⑧❜❤✭❪✆❚❬❫❜♣✱❙➙❿✷◆➌♦✼➔ ▼✚❯
➔❸❙❘➣☛❚✦❳✬♣✻❞✞❫✆❪❅❳✱❚✞❣✥❚✦➉✚❿▲♦✼❳✬♣✻❙❇❫✧♣✛♦✠r❅❞❊❞✞❫P❪❍❪✆❚✞❫✆❪✚❳✱❙➙❿❷❚❼♣✻❤✆❞✚♣①➣✼❚✞❚✞❫s❪✆❚P♣✛❣✦❳✱❙❘➣☛❚✞❪❍❙❇❫➜❿✷❤✆❚❵❳✱❙✎r ♦✆➔✸♣➎❿✷❳❷❙❇♦●♣✛♦✠r❅❚❼♣➞➄➎❝✯❞✕➐❜❞❬➣
❚✵❿✻❞✦❖➂ ✖✕✗✕ ④✚➅ ➂✆❴➊❤✆❙✮♣➞❞✦❳❸❳✱❞✦❫➁⑧❜❚✞r❍❚✞❫✥❿✻❣✞♦✼❫✥❿✷❳✱❞❼♣✮❿✱♣ ✠❧❙➙❿✷❤❅❿✷❤✆❚➜♣❸❿✷❳❸❙❉❞✵❿❷❞✞❖✪♣✱❚✞❫✠♣✛♦✼❳✱❙❇r❅♦✚❿❷♦✚❳✸r❅❞✵❿✷❳❷❙❉➇ ✠❅❤✆❚✕❳✱❚✞❩✏❞❼♣✄❙❇❫➜❿✷❤❜❚
♦❼❿✷❤✆❚✕❳①➣✆❳✱❞✞❙❇❫➋♣➎❿✷❳➎❥☛❣✬❿✮❥❜❳✱❚❼♣✛❩✼❿✷❤✆❚✦❳✛❚❑❙✮♣✄❫P♦■❣✞♦✆❫✠♣✱❙✮♣✷❿❷❚❬❫✥❿❛❳✱❚✞❖❇❞✵❿❷❙✑♦✼❫❜♣❸❤✆❙❇➉■➣❜❚✯❿✠❅❚✞❚✕❫❍❿✷❤✆❚❊❞✞r❅♦✚❥✌❫✥❿✻♦✼➔✄▼✚❯↔❳✱❚✞❣✥❚✦➉✚❿▲♦✼❳★♣
HAL author manuscript inserm-00165788, version 1
❺❜➀✆➀✆➀✚➅✯➂✆❢✰♦✚❳✱❚✕♦P◗✼❚✦❳✱❩✽❞❼♣✝✠❅❚❊❳✱❚❋❣✞❚✞❫❼❿✷❖❘◆ ♣✱❤P♦ ✠❑❚✞❪✆❩✏❙✹❫❍❿✷❤❜❚❅❖❇❙✎r❊➣✌❙✑❣✎☛✑❯✏⑩✿❿❷❚✕❳❸❳✱❙➙❿❷♦✚❳➎◆✭♦❜➔➊❿✷❤P❚➜❪✆♦✆❳✬♣✛❞❬❖↕♣✷❿✷❳➏❙❉❞✵❿✮❥✌r❑❩✪❙✎❫
❞✞❪✆❪✆❙➙❿❷❙❇♦✼❫ ❿❷♦ ❿✷❤✆❚■✐❧❭ ☛✎✐❧❺✢❙❇❫✆❤✆❙❘➣✌❙➙❿❷♦✆❳❸◆✰❣✞♦✆❫❼❿✷❳❷♦✆❖③♦❜➔❊❭✤⑥❱❤⑨❳✱❚✞❖✑❚✞❞❼♣★❚❋❩➞✈
✉ q ❖❉♦✠❣✞❞✞❖✑❖✹◆✰❳✱❚✞❖✑❚✞❞❼♣✛❚✞❪♠➣✆◆ ♦✚❥✆❿✷➉✚❥✚❿
❫✆❚✯❥❜❳✱♦✼❫❜♣✭❙✹❫✆❤✆❙❘➣☛❙➙❿★♣➝❭✤⑥❱❤✢❳✛❚❬❖✑❚✞❞✥♣✱❚✿❿✷❤✚❳✛♦P❥❜⑧✆❤✢r✤❥➛♦✆➉❜❙❇♦✠❪✰❳✱❚✞❣✞❚✦➉✚❿▲♦✼❳★♣➝➄▲❢♠➠❶✇✤♣❷➅➝❖❇♦✠❣❋❞✵❿❷❚✞❪✢♦✆❫✢❣✞❤P♦✠❖❇❙✹❫❜❚✕❳❸⑧✠❙✑❣
❙❇❫❼❿❷❚✦❳✱❫P❚✵❥❜❳✱♦✆❫✆❚❼♣ ➂ t
❫❼❿❷❚✦❳✱❚✥♣➎❿✷❙❇❫✚⑧❜❖✹◆P❩ ❿✷❤P❚♠✈
✉ q ☛✮❢✰➠③✇ ❳✱❚✕⑧✼❥☛❖❇❞✵❿❷❙❇♦✆❫ ♦❜➔➝❭❊⑥✸❤ ❳✛❚❬❖✑❚✞❞✥♣★❚♠➉✆❳✱❚✥♣✱❚✞❫❼❿✱♣➌❞✰❪✼❙❘❥❜❳✱❫❜❞❼❖
◗❜❞✕❳➏❙✑❞✵❿❷❙❇♦✆❫✆❩✼➣✼❚✞❙✹❫✆⑧❏♦✼❫✆❖❇◆❏❚❬➔✷➔❸❙✑❣✞❙✑❚❬❫✥❿❛❙❇❫❑❿✷❤P❚❾❖✑❞❼♣➎❿❀➉❜❞✦❳➎❿❀♦✆➔✳❿✷❤✆❚✤❖✹❙❇⑧❜❤❼❿❀➉❜❚✦❳❸❙❇♦❜❪❍➄➎❝ ❞✵➣❜♦✚❥❜❳✱❙❇❞✞❫✝☛✍✌ ✎✒✑✚✓✌❺❜➀✆➀ ➆ ❽✆❺❜➀✆➀✠❹✥➅ ➂
❴↕❤❼❥✏♣✱❩↕❙❇❫■❿✷❤✆❚❍❖✑❙✎r❊➣☛❙✎❣✌☛✎❯✏⑩⑨❿❷❚✦❳❸❳❸❙→❿❷♦✚❳➎◆P❩✳❿✷❤✆❚➝❚✞➔➎➔❷❚✞❣✵❿❷❙❘◗❜❚✞❫✆❚✚♣★♣✤♦✼➔❛❿✷❤✆❚❍❪✆❙❇❳✱❚✞❣✵❿✻❿❷❞✞❣✦❤✚◆✆➐❜❙❇❫✆❙❇❫☞☛✉ qs➢❛❳✱❚✦⑧✚❥☛❖✎❞✯❿❸❙❇♦✆❫➌♦●➔
❭✤⑥❱❤➝❳✛❚❬❖✑❚✞❞✥♣✱❚➜r❅❙❇⑧❜❤❼❿❛➣❜❚❍♣➎❥❜➣❜r❅❙➙❿✮❿❷❚✞❪➜❿✷♦✭❞❊❪✆❙➙❥❜❳✱❫✆❞✞❖✳◗✼❞✦❳✱❙✑❞❋❿✷❙❉♦✼❫❏❪❼❥☛❚ ❿❷♦✧❙→❿✱♣✸➉❜♦✌♣✬♣✱❙❘➣✌❖✑❚❊❙❇❫❼❿❷❚✦❳✛❞✞❣✵❿❷❙❇♦✼❫ ✠❅❙➙❿❷❤➜❿✷❤❜❚
✈ ✉ q ☛✑❢✰➠ ✇✰❿✷❳✱❞✦❫❜♣✱r➜❙✮♣✯♣✱❙❇♦❜❫✌➂
❴↕❤✆❚✦❳✱❚✞➔✷♦✆❳✱❚✞❩❾❿✷❤✆❚✰➉✆❳✱❚❼♣✱❚✕❫❼❿➋♣➎❿✮❥☛❪✚◆ ✠❅❞✥♣❁❥✌❫P❪✆❚✦❳➎❿❷❞✦➐❜❚✦❫➟❿❷♦✏➃ ❡❁❪✆❚✯❿❷❚✦❳❸r❅❙❇❫❜❚ ✠❅❤✆❚✯❿✷❤✆❚✦❳✱❩❅❙❇❫✓❿✷❤✆❚✢❖✑❙✎r❊➣✌❙✑❣✎☛✑❯✪⑩
❿❷❚✦❳✷❳❸❙➙❿❷♦✆❳➎◆ ♦✆➔ ❳✱❞✵❿ ❪➁♦✼❳★♣✱❞✦❖ ♣➎❿✷❳✱❙❇❞✵❿✮❥☛r❅❩➛❣✦❤P♦✠❖❇❙✹❫❜❚✕❳❸⑧✠❙❉❣ ❙✎❫❼❿❷❚✕❳❸❫✆❚✵❥❜❳✛♦✼❫P❚❼♣ ❚✦➇P➉✆❳✱❚❼♣✯♣ ✉ qs➢✎✇✤♣ ❞✥♣ ❙❇❫ ❿✷❤❜❚
♣✱❚✞❫❜♣✱♦✆❳➏❙❇r❅♦✚❿✷♦✆❳➜❿❷❚✕❳➎❳❸❙→❿❷♦✼❳➎◆ ❞✞❫✆❪➟❙✎➔➜❿✷❤P❚❼♣✱❚ ❳✛❚✞❣✥❚✦➉✚❿✷♦✆❳✬♣✭❞✦❳✛❚⑨❣✞♦✠❡❷❚✵➇✆➉✆❳✱❚✥♣✬♣✱❚❋❪ ✠❑❙➙❿❸❤✰❢✰➠ ✇✤♣➝❺❜❡➝❞✞❫✆❞✞❖❇◆✆❨➁❚✿❿✷❤✆❚
r❅♦❜❪❼❥✌❖✑❞✵❿❷❙❇♦✆❫✭❚✦➇❜❚✦❳➎❿❷❚❋❪❏➣✆◆➝❿❷❞✞❣✕❤✚◆✆➐❜❙✹❫❜❙❇❫✌♣❱◗❜❙✑❞
✉
qs➢✹✇❧♣ ♦✼❫➝❿✷❤✆❚❊❳✱❚✞❖❇❚❋❞P♣✛❚❅♦✼➔✸❭❧⑥❱❤✭❞✞❫P❪■❙➙❿✱♣ ❙✹❫✥❿❷❚✦❳✱❞✞❣✯❿❸❙❇♦✆❫ ✠❅❙➙❿❷❤
❿✷❤✆❚❅❙❇❫✆❤✆❙❉➣☛❙➙❿❷♦✆❳➎◆❍✈ ✉ q ☛✑❢✰➠③✇ ❿✷❳✱❞✦❫❜♣✱r❍❙✮♣✯♣✱❙❇♦✠❫✭❻✆❡✄❪✆❚✵❿❷❚✕❳❸r❅❙✎❫✆❚❾❿✷❤P❚❏♣✷❥✠➣➁❿➎◆➁➉❜❚❅♦✠➔❛❳✱❚✞❣✞❚✕➉✚❿❷♦✚❳✬♣③❙❇❫✚◗✼♦✠❖❘◗❜❚✞❪■❙❇❫❍❿✷❤❜❚
❿❷❞✞❣✦❤✚◆➁➐❜❙❇❫✠❙❇❫
✉
qs➢✹✇ ❳✱❚✦⑧✚❥☛❖✑❞✵❿✷❙❇♦✆❫✌➂➜✇❶❚✞❖✑❚✞❞✚♣✱❚✞❪ ♣➎❿✮❥☛❪✆❙❇❚✚♣ ✠❑❚✦❳✱❚ ❪✆♦✼❫P❚ ❙❇❫ ♣✱❙➙❿✮❥☛❞✵❿❷❙❇♦✼❫ ♦✆➔✿✐❅❭ ❪✆❚✦➉❜❖✎❚✯❿❸❙❇♦✆❫
❳✱❚✑✏❼❥☛❙❘❳✱❚❋❪❧❿▲♦❊♦✚➣✌♣✱❚✕❳✛◗✼❚❱❿✷❤✆❚❵❪✆❙❘❳✱❚✞❣✯❿✌❿❷❞✞❣✦❤✚◆P➐✠❙❇❫✆❙❇❫❅❳✱❚✦⑧✚❥☛❖✎❞✯❿✷❙❇♦✼❫❑♦✼➔✽❣✞❤✆♦✠❖❇❙❇❫❜❚✦❳❸⑧❜❙✑❣❱❿✷❳✱❞✦❫❜♣✱r➜❙✮♣✯♣✱❙❇♦❜❫✌➂
✁✂✁ ✆ ☎✄ ✄ ✁✟✆✆✝✁ ✁✂✞✫✄✝✆ ✄
✈❛➇✆➉❜❚✦❳✱❙❇rs❚❬❫✥❿✱♣ ✠❑❚✦❳✱❚③➉❜❚✦❳✱➔✷♦✆❳❸r❅❚✞❪❅♦✆❫➝▼✆➉✆❳✱❞✦⑧✚❥☛❚✞❡▲✐❑❞✎✠❅❖❉❚❋◆srs❞✞❖✑❚③❳✱❞✵❿✱♣❛➄➎❺✆❺✌❹➁❡✷❺✌❹➁➀✚⑧✆❩❜⑥➞❤P❞✦❳✱❖❇❚✚♣✪✇❵❙❘◗☛❚✦❳✛❩P⑩✏❳✛❞✦❫✆❣✥❚✦➅
❿✷❳✱❚✞❞✬❿❷❚✞❪❍❙❇❫➝❞❋❣✞❣✞♦✆❳✱❪✆❞✦❫✆❣✥❚ ✠❑❙➙❿✷❤➜❿✷❤❜❚✡✗③❥☛❙❇❪✠❚❊➔✷♦✆❳✄⑥✄❞✦❳✱❚❊❞✕❫✆❪❍②❍♣✛❚❊♦✼➔↕♥✻❞✦➣❜♦✆❳✱❞✵❿▲♦✚❳➎◆➝❭✤❫✆❙✎rs❞✞❖✮♣ ❚❼♣➎❿❷❞✵➣❜❖✑❙✮♣✱❤❜❚✞❪✧➣❜◆
❿✷❤✆❚ ✉ ❞✵❿✷❙❉♦✼❫P❞❬❖ t ❫✌♣➎❿✷❙→❿✮❥✆❿❷❚❾♦✆➔ ✆s❚✞❞✞❖➙❿✷❤✭❞✞❫✆❪ ✠❑❙➙❿❸❤❅❿✷❤✆❚ ✈❛❥❜❳✱♦✚➉❜❚✞❞✕❫✭⑥❱♦❜r➜r❊❥☛❫✆❙➙❿✷◆✭⑥✄♦P❥❜❫P❣✞❙✎❖✌✐❅❙❇❳✱❚✞❣✵❿❷❙❘◗❜❚ ✙➁④ ☛▲④✆➀ ✕
✈❛✈✄⑥❵➂✪❭✤❖❇❖✄❚✞➔➎➔✷♦✆❳➎❿✱♣ ✠❅❚✕❳✱❚■rs❞✞❪✆❚❍❿❷♦ r➜❙❇❫✆❙✑r❍❙❇❨➁❚■❞✞❫✆❙✎rs❞✞❖❵♣➎❥☛➔➎➔❷❚✦❳✱❙❇❫✚⑧✰❞✞❫✆❪↔♦✼❫✆❖❇◆➋❿✷❤✆❚■❫✥❥✌r❊➣☛❚✦❳❧♦✼➔❶❞✞❫✆❙✎rs❞✞❖➎♣
❫✆❚❋❣❼❚✥♣✬♣★❞✦❳❸◆❊❿❷♦❍➉✆❳❷♦✠❪❼❥☛❣❋❚ ❳✱❚✕❖✹❙✑❞✦➣❜❖✑❚❾❪❜❞✵❿❷❞ ✠❅❞✥♣➊❥✏♣✛❚✞❪✌➂✆❭❾❫✆❙✑r➝❞✞❖✮♣ ✠❅❚✦❳✛❚❾rs❞❬❙❇❫✥❿❷❞❬❙❇❫❜❚✞❪s♦✼❫s❞ ❺❜❡ ❺❜❤❍❖✎❙❇⑧❜❤❼❿ ☛▲❪✆❞✦❳❸➐
➄❸❖❇❙❘⑧✠❤✥❿✱♣s♦✼❫ ❞✵❿❑➀✆⑤✏➃➙➀✆➀⑨❤✚➅✡✠❅❙➙❿❷❤✰➔➎❳✱❚❋❚ ❞✞❣✞❣❋❚P♣★♣❊❿❷♦➓➔✷♦❜♦✠❪✰❞✦❫✆❪ ✠❅❞✵❿❷❚✕❳✯➂✸❴↕❤✆❚✦◆ ✠❑❚✦❳✱❚ ♣★❞✞❣✦❳✱❙❇➔❸❙✑❣✞❚✞❪➓➣✆◆ ❚✞❙➙❿❷❤✆❚✦❳
❪✆❚✞❣✞❞✕➉✠❙➙❿❷❞✯❿✷❙❇♦✼❫ ➄➎❳✱❚✞❖✑❚✞❞❼♣★❚➛❚✦➇✆➉❜❚✦❳✱❙❇rs❚✞❫❼❿✱♣❸➅✰♦✆❳✰❞ ❖❇❚✵❿✷❤P❞✞❖➋❪✆♦●♣✛❚➛➄ ❺❜➀ r❊⑧✏➂q✤⑧✠✟
➢
❩■❙➂➉✏➂➑➅ ♦✼➔➋➉❜❚✞❫❼❿❷♦✚➣❜❞✦❳✷➣❜❙➙❿❷❞❼❖
HAL author manuscript inserm-00165788, version 1
➄✬▼❜❞✦❫P♦✼➔✷❙✑❡✬▼✼◆P❫❼❿✷❤❜❚✞❖✑❞❋➣✼♦✠❩✠♥❛❙❘➣❜♦✚❥❜❳❸❫P❚✞❩✠⑩✏❳✱❞✞❫✆❣✞❚❋❩✳❙❇r❍r❊❥☛❫✆♦✆❤✆❙▲♣❸❿▲♦✠❣✕❤✆❚✞r❅❙▲♣✷❿✷❳❸◆✚➅➞❞✵❿✻➀ ✕ ➃➙➀✆➀➁❡ ➀✏➃➙➀✆➀❍❤❏➄➎r❅♦✆❳❸❫✆❙❇❫✚⑧✆➅✄♦✆❳
❹☛➃➙➀✆➀✆❡ ④✏➃➙➀✆➀❊❤❅➄❸❞✦➔✎❿❷❚✕❳❸❫✆♦❜♦✼❫➁➅✯➂
✄
☞✎✖✆✂✆✍✏✺✏✩❍✂✆✍✏✺➟✺✏✒✦✗✏✖✆✩✦✾✻✉
❢↔✐❅❭✤❩①✐❅❡➏♣✛❚✦❳✱❙❇❫❜❚✞❩✸❤❜❚❬r❅❙✑❣✞❤✆♦✠❖✑❙❇❫✠❙❘❥☛r❅❡❸❻✆❩
β➔✎❥☛❫✆❞✞❖➙❿✷❳✱❚✦➇✼❞❬r❅❙❇❫❜❚➋➄
β⑩ ✉ ❭❵➅❅❞✞❫P❪ α❡
rs❚✵❿✷❤✚◆❜❖❇❡➎➉❜❡✮❿➎◆➁❳✱♦✌♣✱❙❇❫✆❚➛➄
α❢↔❯❀❴➊➅ ✠❑❚✦❳✱❚➛♦✚➣✚❿❷❞✦❙❇❫P❚✞❪ ➔✷❳✱♦✠r ▼✠❙❘⑧❜rs❞ ❭✤❖✑❪✚❳✱❙✎❣✞❤ ⑥✄❤✆❙✎rs❙✎❚❋❩❏♥ ✢t
♣✱❖✎❚➛❪ ✢✎❭❵➣❜❚✞❞✯❥☛❩
⑩✏❳✱❞✞❫P❣✞❚➋❞❬❫P❪ ✒✂ ✆ ✕❷❡❸❣✦❤✆♦✆❖❇❙❇❫❜❚✿➔✮❳✱♦✠r ❯❀❚✦❳❸➐❜❙❇❫ ✈✄❖❇rs❚✦❳❍❖❇❙✎➔❷❚ ♣✱❣✞❙✑❚✞❫✆❣✞❚✞❩ ⑥✄♦P❥❜❳✮❿❷❞✵➣❜♦❜❚✵❥❜➔✷❩✸⑩✏❳✱❞✞❫✆❣✞❚➁➂③▼✏▼✚✇③❺ ➆ ➀✆④✆➀✆➀
✠❑❚✦❳✱❚✓➐❜❙❇❫✆❪✆❖✹◆❃⑧✠❙❘◗☛❚✞❫ ➣✆◆ ▼❜❞❬❫P♦✼➔✷❙✑❡✬▼✼◆P❫❼❿✷❤❜❚✞❖✑❞✦➣❜♦ ✇❶❚✞❣✦❤✆❚✞❳✱❣✕❤✆❚✞❩➜✇✄❯❀④✆⑤✠❹✍✙➁➀ ➣✆◆ ✇❶❤✁✆❫✆❚ ❯❀♦✚❥❜❖✑❚❬❫P❣ ✠❅❤✆❙✑❖✮❚
✗③✇③❺❜➀✠❹ ⑤ ❩ ✗③✇☎✙✥❺❜❻✆❻
➆ ❩ ✒✹♥❛◆✌♣✄✂❸❩➙❢✰❚✵♥➞❚✵❥ ✔ ❩✉
❖❇❚
➢✆☎
✕✉ q❊❭✤➄
➆ ❡ ➀✚➅ ✠❅❚✕❳✱❚ ♦P➣➁❿❷❞✞❙✹❫P❚✞❪ ➔✮❳✛♦✠r
✉
❚✞♦✌♣❸◆✌♣✷❿❷❚❬r❑❩
▼✚❿✮❳✱❞✥♣➎➣❜♦✚❥❜❳❸⑧❜❩❁⑩✏❳✱❞✦❫P❣✞❚✚➂ ✉ q❧❭✤❩ ✉ ❯✳q❧❩⑨♣✱❚✞❫✚➐✚❿✷❙❉❪✠❚ ✒✹❯✽❳❷♦ ✔ ✕✬▼✚❯ ❞✦❫✆❪ ▼✚❯↕➄❷④✆❡ ✆ ➅❸❩ ✠❅❚✕❳✱❚ ♦✚➣✚❿❷❞✕❙✹❫P❚✞❪ ➔✮❳✱♦✌r
❯❀❚✦❫✆❙❇❫✌♣➎❥☛❖✑❞✞❩
t
❫❼❿❷❚✦❳✱❣✕❤✆❙✎r❅❩✚❢✰♦✆❫❼❿❷❖➙❥✞✝✞♦✆❫✆❩✚⑩✏❳✱❞✞❫✆❣❋❚✚➂
✄ ✜✆☎✞✂✚✘✑☞✠✟✥✂✚✙✛☞✎✜✆✍❁✜✆✣↕✙✱✝✏✔❾✘✑☞✎✫✭✲✏☞✎☎✵✴☛✡✌☞ ✂✆✍✳✺➌✩✯✔✞✍✏✩✬✜❜✒✦☞✮✫✭✜✚✙✱✜✆✒❵✙✱✔✞✒✞✒✕☞✹✙✱✜❜✒✕☞✎✔✥✩✄☞✎✍■✙✱✝✏✔❊✒✕✂✚✙✻✺✳✜❜✒✕✩✬✂✆✘✪✩✱✙✱✒✕☞✎✂✚✙✱✗✏✫➋✾ ❭❍♣
➉✆❳✱❚✵◗❜❙❉♦P❥✏♣✱❖❇◆➝rs❚✞❫❼❿❷❙❇♦✼❫P❚✞❪✆❩✼❿✷❤P❚❶❿▲♦✼➉P♦✼⑧✆❳✱❞✕➉✆❤✆❙❇❣✞❞✞❖✏❞✦❳❸❳✛❞❬❫➁⑧❜❚✞r➝❚✦❫✥❿❛♦✆➔✳❿✷❤✆❚✤❣✞♦✆❳▲❿✷❙❉❣✞♦●♣✷❿✷❳❸❙❇❞✵❿❷❞✞❖❜➉✆❳✱♦ ✄✱❚❋❣✵❿❸❙❉♦✼❫❜♣✸❪✆❚✞➔❸❙❇❫❜❚✚♣
➔✮❥✌❫P❣✵❿❸❙❉♦✼❫P❞❬❖✏❿❷❚✦❳❸❳❸❙→❿❷♦✚❳❸❙❇❚✚♣③❙❇❫➝❿✷❤✆❚❅❪✆♦✆❳✬♣✱❞✞❖↕♣➎❿✷❳✱❙❇❞✵❿✮❥❜r ➄▲➍ ❚✦❳✱❚✦❫❜❪✠♣✛❚☎☛✍✌✩✎✒✑✚✓
✖✕✗✕
❺✌❽✠✐❑❚❬❫✆❙✑❞✵❥ ❞✞❫✆❪✭❴➊❤✆❙✑❚✦❳❷❳✛◆
✖✕✗✕
⑤✚➅ ➂
❴↕❤✆❚■❖❇❙✎r❊➣☛❙✑❣✎☛✎❯✽⑩➓❿❷❚✦❳✷❳❸❙➙❿❷♦✆❳➎◆↔❖❇❙✑❚P♣✤❳✱♦✌♣✮❿✷❳❸♦❜❡➎r❅❚❋❪✼❙✑❞✞❖✎❖❇◆↔❞✞❫✆❪ ❿✷❤P❚ ♣✛❚✞❫✌♣✱♦✆❳❸❙❇r❅♦P❿❷♦✆❳❱❿❷❚✕❳❸❳❸❙➙❿❷♦✚❳➎◆↔❖✑❞✵❿❷❚✦❳✛❞❬❖❇❖❇◆✌➂✻▼✠❞✕⑧✠❙➙❿✮❿❷❞✞❖
♣✱❖❇❙✑❣❼❚✥♣✸➔✷❳✱♦✼r ❿✷❤✆❚❼♣✛❚ ❿ ✠❅♦❊❿❷❚✵❳❷❳❸❙➙❿❷♦✆❳❸❙❇❚❼♣ ✠s❚✦❳✛❚ ➉❜❚✦❳✱➔✷♦✆❳✱r❅❚✞❪❍❞✯❿✪❿✷❤✆❚✤➔✷♦✠❖❇❖❇♦ ✠❑❙✹❫✆⑧❏❣✞♦❜♦✼❳✱❪✚❙❇❫P❞✵❿❷❚❼♣✻❞✞❣✞❣✞♦✆❳✱❪✆❙❇❫✚⑧➜❿❷♦❊❿✷❤✆❚
❞✵❿✷❖❇❞✚♣➞♦✼➔✪❯❀❞✵➇❜❙❇❫✆♦✏♣✄❞✦❫P❪ ✛ ❞✵❿✱♣✱♦✆❫➝➄ ✖✕ ✙➁④✚➅✕➃P♥✻❞✵❿❷❚✯❳✱❞✞❖✏➄▲♥❛➅ ❩✕ ❿▲♦✧❺❜❩✕ ➔✷♦✆❳↕❿✷❤✆❚❾❖❇❙✎r❊➣☛❙✑❣✎☛✎❯✽⑩⑨♣✱❖✎❙✑❣✞❚❼♣➞❞✞❫✆❪➜♥ ➆ ❿✷♦
④❊➔✷♦✼❳✏❿✷❤✆❚❾♣✛❚✦❫✌♣✱♦✆❳❸❙❇r❅♦✚❿❷♦✼❳❛♣✱❖✹❙✑❣✞❚✥♣✯➂
✯✫➌✫■✗✏✍✏✜✆✝✏☞✎✩➏✙✛✜✆☎✞✝✏✔✞✫■☞✑✩➏✙★✒✬✟❁✾
②❧❫✆❪✆❚✦❳ ❪✆❚✞❚✦➉ ➉❜❚✞❫❼❿❷♦✚➣❜❞✕❳➎➣❜❙➙❿❷❞✞❖ ❞✞❫✆❚✚♣✷❿✷❤✆❚❼♣✱❙✑❞✞❩ ❳✱❞✯❿✱♣ ✠❅❚✦❳✛❚ ➉❜❚✦❳❸➔✎❥✽♣✱❚❋❪ ❿✷❳✱❞✦❫❜♣✱❣✞❞✦❳✛❪✼❙✑❞✞❖❇❖✹◆ ✠❅❙➙❿❷❤ ➆✁✍
➉❜❞✦❳✱❞✞➔✷♦✆❳❸r❅❞✞❖✑❪✆❚✞❤✚◆❜❪❜❚ ❙❇❫❅➀✌➂ ❢ ➉❜❤✆♦✌♣❸➉❜❤✆❞✵❿❷❚❱➣➁❥✌➔✷➔❸❚✕❳❛➄▲❯✏➍③➅↕➉ ✆ ⑤✌➂
➆
➂❬➍ ❳✱❞✦❙❇❫❜♣ ✠s❚✦❳✱❚③❳✛❚❬r❑♦P◗✼❚✞❪✆❩✼➉❜♦✌♣➎❿❷❡✷➔➎❙❘➇❜❚❋❪➜❙✎❫
❿✷❤✆❚➋♣✱❞✞rs❚✿➔✷❙❉➇☛❞✯❿❸❙❘◗❜❚➋➔✷♦✼❳❧❺➓❤P♦P❥❜❳✬♣❑❞✵❿ ➆✏✎ ⑥✄❩✄❞✞❫✆❪✰❣✦❳❸◆P♦✼➉✆❳✱♦❼❿❷❚❋❣ ❿❷❚✞❪ ❙❇❫✰❻✆➀ ✍ ♣✷❥☛❣✦❳✱♦✌♣✱❚✚➂✪②s♣✱❙❇❫✆⑧✢❞❁➔✮❳★❚✞❚✦❨✥❙❇❫✠⑧
r❍❙✑❣✦❳✛♦❼❿✷♦✆r❍❚❋❩♠♣✱❚✕❳➏❙❉❞❬❖✰♣✱❞✦⑧❜❙➙❿✮❿❷❞✞❖⑨♣✱❚✞❣✯❿❸❙❇♦✆❫✠♣ ✠❑❚✦❳✱❚ rs❞✞❪✆❚ ❙❇❫ ❿✷❤✆❚ ♣✷❿✷❳➏❙❉❞✵❿✮❥❜r ➄ ❹✒✑✌r ❿✷❤✆❙❇❣✕➐✆➅✯➂✧✐❑♦P❥✆➣❜❖✑❚
❙✎rsr❊❥✌❫P♦✼➔✷❖❘❥☛♦✼❳✱❚✥♣✱❣✞❚✞❫❼❿ ✠❑❚✦❳✱❚✤➉❜❚✦❳❸➔✷♦✆❳❸rs❚✞❪✏➃ ❡✸❣✕❤✆♦✠❖❇❙❇❫❜❚❊❞✞❣✥❚✵❿✮◆P❖●❿✷❳✛❞✦❫✠♣✱➔❷❚✦❳✱❞❼♣✛❚❊➄❸⑥✄❤✆❭✤❴➊➅✱❡★▼P❯ ☛✉
qs➢✹✇❑➃✆➉✆❳➏❙❇rs❞✦❳✱◆
❞✦❫✥❿❸❙❘➣❜♦❜❪✆❙❇❚❼♣✤➔✷♦✼❳❶⑥✸❤✆❭✤❴✓➄ ➃❺✌❹➁➀✆❩↕r❅♦P❥✏♣✛❚❍r❅♦✆❫✆♦❜❣❬❖❉♦✼❫❜❞✞❖❇❩❛⑥✸❤❜❚❬r❅❙✑❣✞♦✆❫✆❩↕❴❛❚✞r❍❚❋❣✵❥✌❖✑❞✞❩✳②❏▼✠❭❵➅❶❞✦❫✆❪⑨▼✚❯ ☛✉ qs➢✎✇
➄ ➃ ➀✆➀✆➀✆❩❑❳✛❞✵➣✚➣❜❙➙❿✭➉❜♦❜❖❉◆✼❣✞❖❇♦✠❫✆❞✞❖❇❩s⑥❱❤P❚❬rs❙✑❣✞♦✼❫P❩❅❴①❚✞r❅❚✥❣✵❥☛❖✮❞✞❩❾②❏▼✆❭❵➅ ✠❅❚✕❳✱❚➓◗❜❙▲♣✷❥☛❞✞❖✎❙❇❨➁❚✞❪✓❥✏♣✱❙❇❫✆⑧ ♣✛❚✞❣✞♦✆❫✆❪✆❞✦❳✱◆
HAL author manuscript inserm-00165788, version 1
