• Aucun résultat trouvé

Increased inhibition of cytochrome P450 3A4 with the tablet formulation of posaconazole

N/A
N/A
Protected

Academic year: 2021

Partager "Increased inhibition of cytochrome P450 3A4 with the tablet formulation of posaconazole"

Copied!
16
0
0

Texte intégral

(1)

HAL Id: hal-01376262

https://hal-univ-rennes1.archives-ouvertes.fr/hal-01376262

Submitted on 8 Nov 2016

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

L’archive ouverte pluridisciplinaire HAL, est destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d’enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

tablet formulation of posaconazole

A. Petitcollin, R. Crochette, C. Tron, C. Verdier, C. Boglione-Kerrien, C.

Vigneau, E. Bellissant, F. Lemaitre

To cite this version:

A. Petitcollin, R. Crochette, C. Tron, C. Verdier, C. Boglione-Kerrien, et al.. Increased inhi-bition of cytochrome P450 3A4 with the tablet formulation of posaconazole. Drug Metabolism and Pharmacokinetics, Japanese Society for the Study of Xenobiotics, 2016, 31 (5), pp.389 - 393. �10.1016/j.dmpk.2016.05.001�. �hal-01376262�

(2)

M

ANUS

C

R

IP

T

ACCEP

TED

WĂŐĞϭŽĨϭϯ

/ŶĐƌĞĂƐĞĚŝŶŚŝďŝƚŝŽŶŽĨĐLJƚŽĐŚƌŽŵĞWϰϱϬϯϰǁŝƚŚƚŚĞƚĂďůĞƚĨŽƌŵƵůĂƚŝŽŶ

ŽĨƉŽƐĂĐŽŶĂnjŽůĞ

WĞƚŝƚĐŽůůŝŶ͘ϭ͕Ϯ͕ϯ͕ƌŽĐŚĞƚƚĞZ͘ϰ͕dƌŽŶ͘ϭ͕Ϯ͕ϯ͕sĞƌĚŝĞƌDͲ͘ϭ͕Ϯ͕ϯ͕ŽŐůŝŽŶĞͲ<ĞƌƌŝĞŶ͘ϭ͕sŝŐŶĞĂƵ ͘ϰ͕ĞůůŝƐƐĂŶƚ͘ϭ͕Ϯ͕ϯ͕>ĞŵĂŝƚƌĞ&͘ϭ͕Ϯ͕ϯ ƵƚŚŽƌƐ͛ĂĨĨŝůŝĂƚŝŽŶƐ ϭ͘ZĞŶŶĞƐhŶŝǀĞƌƐŝƚLJ,ŽƐƉŝƚĂů͕ĞƉĂƌƚŵĞŶƚŽĨůŝŶŝĐĂůĂŶĚŝŽůŽŐŝĐĂůWŚĂƌŵĂĐŽůŽŐLJĂŶĚ WŚĂƌŵĂĐŽǀŝŐŝůĂŶĐĞ͕WŚĂƌŵĂĐŽĞƉŝĚĞŵŝŽůŽŐLJĂŶĚƌƵŐ/ŶĨŽƌŵĂƚŝŽŶĞŶƚĞƌ͕ZĞŶŶĞƐ͕&ƌĂŶĐĞ͘ Ϯ͘ZĞŶŶĞƐϭhŶŝǀĞƌƐŝƚLJ͕&ĂĐƵůƚLJŽĨDĞĚŝĐŝŶĞ͕>ĂďŽƌĂƚŽƌLJŽĨdžƉĞƌŝŵĞŶƚĂůĂŶĚůŝŶŝĐĂů WŚĂƌŵĂĐŽůŽŐLJ͕ZĞŶŶĞƐ͕&ƌĂŶĐĞ͘ ϯ͘/ŶƐĞƌŵ͕/ͲWϭϰϭϰůŝŶŝĐĂů/ŶǀĞƐƚŝŐĂƚŝŽŶĞŶƚĞƌ͕ZĞŶŶĞƐ͕&ƌĂŶĐĞ͘ ϰ͘ZĞŶŶĞƐhŶŝǀĞƌƐŝƚLJ,ŽƐƉŝƚĂů͕ĞƉĂƌƚŵĞŶƚŽĨEĞƉŚƌŽůŽŐLJ͕ZĞŶŶĞƐ͕&ƌĂŶĐĞ͘ ŽƌƌĞƐƉŽŶĚŝŶŐĂƵƚŚŽƌ͗ ŶƚŽŝŶĞWĞƚŝƚĐŽůůŝŶ ZĞŶŶĞƐhŶŝǀĞƌƐŝƚLJ,ŽƐƉŝƚĂů ĞƉĂƌƚŵĞŶƚŽĨůŝŶŝĐĂůĂŶĚŝŽůŽŐŝĐĂůWŚĂƌŵĂĐŽůŽŐLJĂŶĚWŚĂƌŵĂĐŽǀŝŐŝůĂŶĐĞ͕ WŚĂƌŵĂĐŽĞƉŝĚĞŵŝŽůŽŐLJĂŶĚƌƵŐ/ŶĨŽƌŵĂƚŝŽŶĞŶƚĞƌ ϮƌƵĞ,ĞŶƌŝůĞ'ƵŝůůŽƵdž͕ϯϱϬϯϯZĞŶŶĞƐĐĞĚĞdž͕&ƌĂŶĐĞ dĞů͗ϬϬϯϯϮϮϯϮϯϰϳϭϯ &Ădž͗ϬϬϯϯϮϵϵϮϴϰϭϴϰ ŵĂŝů͗ĂŶƚŽŝŶĞ͘ƉĞƚŝƚĐŽůůŝŶΛĐŚƵͲƌĞŶŶĞƐ͘Ĩƌ 

(3)

M

ANUS

C

R

IP

T

ACCEP

TED

WĂŐĞϮŽĨϭϯ

ďƐƚƌĂĐƚ

ĞŝŶŐĂƐƵďƐƚƌĂƚĞŽĨƚŚĞĐLJƚŽĐŚƌŽŵĞWϰϱϬϯϰ;zWϯϰͿŝƐŽĞŶnjLJŵĞ͕ƐŝƌŽůŝŵƵƐŵĞƚĂďŽůŝƐŵŝƐ ĚĞĐƌĞĂƐĞĚǁŚĞŶƉŽƐĂĐŽŶĂnjŽůĞŝƐĂĚŵŝŶŝƐƚĞƌĞĚĐŽŶĐŽŵŝƚĂŶƚůLJ͘,ŽǁĞǀĞƌ͕ďĞĐĂƵƐĞŽĨƚŚĞƉŽŽƌ ďŝŽĂǀĂŝůĂďŝůŝƚLJŽĨƚŚĞŽƌĂůƐƵƐƉĞŶƐŝŽŶŽĨƉŽƐĂĐŽŶĂnjŽůĞǁŝƚŚǁŚŝĐŚůŽǁƉůĂƐŵĂĐŽŶĐĞŶƚƌĂƚŝŽŶƐ ĂƌĞŽďƚĂŝŶĞĚ͕zWϯϰŝŶŚŝďŝƚŝŽŶŝƐǁĞĂŬĂŶĚĂϱϬͲϳϱйĚŽƐĞƌĞĚƵĐƚŝŽŶŽĨƐŝƌŽůŝŵƵƐŝƐ ƐƵĨĨŝĐŝĞŶƚƚŽĂǀŽŝĚƐŝƌŽůŝŵƵƐŽǀĞƌĚŽƐĂŐĞ͘dŚĞŶĞǁƚĂďůĞƚĨŽƌŵƵůĂƚŝŽŶĂůůŽǁƐƌĞĂĐŚŝŶŐ ƉŽƐĂĐŽŶĂnjŽůĞĐŽŶĐĞŶƚƌĂƚŝŽŶƐϯƚŽϰĨŽůĚŚŝŐŚĞƌƚŚĂŶƚŚŽƐĞŽďƚĂŝŶĞĚǁŝƚŚƚŚĞŽƌĂů ƐƵƐƉĞŶƐŝŽŶ͘ĂƐĞĚŽŶĂĐĂƐĞŽĨƐŝƌŽůŝŵƵƐŽǀĞƌĚŽƐĂŐĞĨŽůůŽǁŝŶŐƉŽƐĂĐŽŶĂnjŽůĞƚĂďůĞƚƐ ĂĚŵŝŶŝƐƚƌĂƚŝŽŶ͕ǁĞŵŽĚĞůĞĚƚŚĞŝŶŚŝďŝƚŝŽŶŽĨƐŝƌŽůŝŵƵƐĐůĞĂƌĂŶĐĞďLJƉŽƐĂĐŽŶĂnjŽůĞ͕ĂŶĚƚŚĞŶ ƐŝŵƵůĂƚĞĚƐĞǀĞƌĂůĚŽƐĂŐĞƌĞŐŝŵĞŶƐŽĨƐŝƌŽůŝŵƵƐƚĂŬĞŶƚŽŐĞƚŚĞƌǁŝƚŚƉŽƐĂĐŽŶĂnjŽůĞƚĂďůĞƚƐ͘ tĞǁĞƌĞĂďůĞƚŽĚĞƐĐƌŝďĞǁĞůůƚŚĞŝŶƚĞƌĂĐƚŝŽŶ͕ĂŶĚĨŽƵŶĚĂǀĂůƵĞŽĨ/ϱϬŽĨƉŽƐĂĐŽŶĂnjŽůĞ ƚŽǁĂƌĚƐƐŝƌŽůŝŵƵƐĐůĞĂƌĂŶĐĞŽĨϬ͘ϲϴђŐͬŵ>͘dŚĞƐŝŵƵůĂƚŝŽŶƐƐŚŽǁĞĚƚŚĂƚĞǀĞŶĂϴϬй ĚĞĐƌĞĂƐĞŽĨƚŚĞĚĂŝůLJĚŽƐĞŽĨƐŝƌŽůŝŵƵƐŝƐƵŶƐƵŝƚĂďůĞŝŶŵĂŶLJĐĂƐĞƐǁŝƚŚƚƌŽƵŐŚ ĐŽŶĐĞŶƚƌĂƚŝŽŶƐŽĨƉŽƐĂĐŽŶĂnjŽůĞŽĨϮђŐͬŵ>͘ĚĞĐƌĞĂƐĞŽĨϰϬйŽĨƚŚĞĚŽƐĞǁŝƚŚƐƉĂĐŝŶŐ ĂĚŵŝŶŝƐƚƌĂƚŝŽŶƐŽĨϯĚĂLJƐŵĂLJďĞĐŽŶƐŝĚĞƌĞĚ͘dŚĞĐůŝŶŝĐŝĂŶƐĂŶĚƉŚĂƌŵĂĐŽůŽŐŝƐƚƐŵƵƐƚďĞ ǁĂƌŶĞĚƚŚĂƚƚŚĞƵƐĞŽĨƉŽƐĂĐŽŶĂnjŽůĞƚĂďůĞƚƐŵĂLJƌĞƐƵůƚŝŶĂŶŝŶŚŝďŝƚŝŽŶŽĨzWϯϰŽĨŐƌĞĂƚĞƌ ŵĂŐŶŝƚƵĚĞƚŚĂŶǁŝƚŚƚŚĞŽƌĂůƐƵƐƉĞŶƐŝŽŶ͘



<ĞLJǁŽƌĚƐ

^ŝƌŽůŝŵƵƐ͕ƉŽƐĂĐŽŶĂnjŽůĞ͕ĚƌƵŐͲĚƌƵŐŝŶƚĞƌĂĐƚŝŽŶ͕ƉŚĂƌŵĂĐŽŬŝŶĞƚŝĐƐ͕ĐLJƚŽĐŚƌŽŵĞWͲϰϱϬzWϯ  

(4)

M

ANUS

C

R

IP

T

ACCEP

TED

WĂŐĞϯŽĨϭϯ

/ŶĐƌĞĂƐĞĚŝŶŚŝďŝƚŝŽŶŽĨĐLJƚŽĐŚƌŽŵĞWϰϱϬϯϰǁŝƚŚƚŚĞƚĂďůĞƚĨŽƌŵƵůĂƚŝŽŶ

ŽĨƉŽƐĂĐŽŶĂnjŽůĞ

 /ŶƚƌŽĚƵĐƚŝŽŶ WŽƐĂĐŽŶĂnjŽůĞŝƐĞdžƚĞŶƐŝǀĞůLJƵƐĞĚŝŶƚƌĂŶƐƉůĂŶƚƉĂƚŝĞŶƚƐƚŽƉƌĞǀĞŶƚĂŶĚƚŽƚƌĞĂƚĨƵŶŐĂů ŝŶĨĞĐƚŝŽŶƐ͘ƐŽƚŚĞƌĂŶƚŝĨƵŶŐĂůƚƌŝĂnjŽůĞĚƌƵŐƐ͕ƉŽƐĂĐŽŶĂnjŽůĞŝƐĂŶŝŶŚŝďŝƚŽƌŽĨƚŚĞĐLJƚŽĐŚƌŽŵĞ WϰϱϬ;zWͿϯϰŝƐŽĞŶnjLJŵĞ͘/ƚǁĂƐƌĞƉŽƌƚĞĚƚŽŝŶĐƌĞĂƐĞƐŝƌŽůŝŵƵƐĞdžƉŽƐƵƌĞďLJϴ͘ϵĨŽůĚŝŶ ŚĞĂůƚŚLJǀŽůƵŶƚĞĞƌƐĂŶĚƚŽŝŶĐƌĞĂƐĞƐŝƌŽůŝŵƵƐĐŽŶĐĞŶƚƌĂƚŝŽŶͬĚŽƐĞƌĂƚŝŽďLJϮ͘ϳĨŽůĚŝŶ ŚĞŵĂƚŽƉŽŝĞƚŝĐƐƚĞŵĐĞůůƚƌĂŶƐƉůĂŶƚƌĞĐŝƉŝĞŶƚƐ͕ǁŚĞŶĂĚŵŝŶŝƐƚĞƌĞĚĂƐĂϰϬϬŵŐŽƌĂů ƐƵƐƉĞŶƐŝŽŶ/ϭ͕Ϯ͘dŚĞƌĞĨŽƌĞ͕ǁŚĞŶĐŽͲĂĚŵŝŶŝƐƚƌĂƚŝŽŶĐĂŶŶŽƚďĞĂǀŽŝĚĞĚ͕ƌĞĚƵĐƚŝŽŶƐŽĨϱϬƚŽ ϳϱйŽĨƚŚĞƐŝƌŽůŝŵƵƐĚŽƐĞǁĞƌĞƉƌŽƉŽƐĞĚĂƚƉŽƐĂĐŽŶĂnjŽůĞŝŶŝƚŝĂƚŝŽŶǁŝƚŚĐůŽƐĞŵŽŶŝƚŽƌŝŶŐŽĨ ƚŚĞĐŽŶĐĞŶƚƌĂƚŝŽŶƐĂŶĚƐƵďƐĞƋƵĞŶƚĚŽƐŝŶŐĂĚĂƉƚĂƚŝŽŶƐϭ͕ϯ͘ WŚĂƌŵĂĐŽŬŝŶĞƚŝĐƐƚƵĚŝĞƐĚĞŵŽŶƐƚƌĂƚĞĚĂĨĂƐƚĞƌĂĐŚŝĞǀĞŵĞŶƚŽĨŚŝŐŚĞƌĐŽŶĐĞŶƚƌĂƚŝŽŶƐǁŝƚŚ ƚŚĞŶĞǁƚĂďůĞƚĨŽƌŵƵůĂƚŝŽŶŽĨƉŽƐĂĐŽŶĂnjŽůĞƚŚĂŶǁŝƚŚƚŚĞŽƌĂůƐƵƐƉĞŶƐŝŽŶϰ͘'ŝǀĞŶƚŚĂƚ ƚƌŝĂnjŽůĞĚƌƵŐƐƵƐƵĂůůLJŝŶŚŝďŝƚzWϰϱϬŝƐŽĞŶnjLJŵĞƐŝŶĂĐŽŶĐĞŶƚƌĂƚŝŽŶͲĚĞƉĞŶĚĞŶƚŵĂŶŶĞƌ͕ ĚƌƵŐͲĚƌƵŐŝŶƚĞƌĂĐƚŝŽŶĂƌĞĞdžƉĞĐƚĞĚƚŽďĞŽĨŐƌĞĂƚĞƌŵĂŐŶŝƚƵĚĞǁŝƚŚƉŽƐĂĐŽŶĂnjŽůĞƚĂďůĞƚƐ͘ ,ŽǁĞǀĞƌ͕ŶŽŝŶƚĞƌĂĐƚŝŽŶƐƚƵĚLJŚĂƐĞǀĞƌďĞĞŶƌĞƉŽƌƚĞĚǁŝƚŚƚŚŝƐŶĞǁƚĂďůĞƚĨŽƌŵƵůĂƚŝŽŶ͘dŚŝƐ ŝƐƐƵĞŵĂLJŚŽǁĞǀĞƌďĞŽĨƵƚŵŽƐƚŝŵƉŽƌƚĂŶĐĞ͕ĂƐĚĞŵŽŶƐƚƌĂƚĞĚďLJƚŚĞĐĂƐĞǁĞƌĞƉŽƌƚŚĞƌĞ͘ ĂƐĞĚŽŶƚŚŝƐĐĂƐĞ͕ǁĞŵŽĚĞůĞĚƚŚĞĂůƚĞƌĂƚŝŽŶŽĨƐŝƌŽůŝŵƵƐĐůĞĂƌĂŶĐĞĨŽůůŽǁŝŶŐ ĂĚŵŝŶŝƐƚƌĂƚŝŽŶŽĨƉŽƐĂĐŽŶĂnjŽůĞ͘dŚĞƌĞůĞǀĂŶĐĞŽĨĐƵƌƌĞŶƚƌĞĐŽŵŵĞŶĚĂƚŝŽŶƐƌĞŐĂƌĚŝŶŐĚŽƐĞ ĂĚũƵƐƚŵĞŶƚƐĂƌĞĚŝƐĐƵƐƐĞĚĂŶĚĐŽŶĨƌŽŶƚĞĚƚŽƉŚĂƌŵĂĐŽŬŝŶĞƚŝĐƐŝŵƵůĂƚŝŽŶƐ͘ WĂƚŝĞŶƚĂŶĚŵĞƚŚŽĚƐ ĂƐĞƌĞƉŽƌƚ

(5)

M

ANUS

C

R

IP

T

ACCEP

TED

WĂŐĞϰŽĨϭϯ ϮϯͲLJĞĂƌͲŽůĚŬŝĚŶĞLJƚƌĂŶƐƉůĂŶƚƉĂƚŝĞŶƚƚƌĞĂƚĞĚǁŝƚŚƐŝƌŽůŝŵƵƐϱŵŐĚĂŝůLJ;YͿƌĞĐĞŝǀĞĚƚŚĞ ƌĞĐŽŵŵĞŶĚĞĚƚĂďůĞƚƐƚƌĞĂƚŵĞŶƚƌĞŐŝŵĞŶŽĨƉŽƐĂĐŽŶĂnjŽůĞ͕ĐŽŶƐŝƐƚŝŶŐŽĨĂϲϬϬŵŐůŽĂĚŝŶŐ ĚŽƐĞŽŶƚŚĞĨŝƌƐƚĚĂLJĂŶĚƚŚĞŶϯϬϬŵŐY͕ĨŽƌƐĞĐŽŶĚĂƌLJƉƌĞǀĞŶƚŝŽŶŽĨŝŶǀĂƐŝǀĞĨƵŶŐĂů ŝŶĨĞĐƚŝŽŶ͘ĞĨŽƌĞƚŚĞŝŶƚƌŽĚƵĐƚŝŽŶŽĨƉŽƐĂĐŽŶĂnjŽůĞ͕ƐŝƌŽůŝŵƵƐƚƌŽƵŐŚĐŽŶĐĞŶƚƌĂƚŝŽŶƐƌĂŶŐĞĚ ďĞƚǁĞĞŶϳĂŶĚϭϬŶŐͬŵ>͘'ŝǀĞŶƚŚĞůĂĐŬŽĨĞdžƉĞƌŝĞŶĐĞǁŝƚŚƉŽƐĂĐŽŶĂnjŽůĞƚĂďůĞƚƐĂŶĚƚŚĞ ůŽǁƉŽƐĂĐŽŶĂnjŽůĞƚƌŽƵŐŚĐŽŶĐĞŶƚƌĂƚŝŽŶƐŽďƚĂŝŶĞĚǁŝƚŚƚŚĞŽƌĂůƐƵƐƉĞŶƐŝŽŶĨŽƌŵĞƌůLJƵƐĞĚŝŶ ŽƵƌĐĞŶƚĞƌ͕ŽŶůLJĂƐŵĂůůŝŶĐƌĞĂƐĞŝŶƐŝƌŽůŝŵƵƐĐŽŶĐĞŶƚƌĂƚŝŽŶƐǁĂƐĞdžƉĞĐƚĞĚĂĨĞǁĚĂLJƐĂĨƚĞƌ ƉŽƐĂĐŽŶĂnjŽůĞŝŶƚƌŽĚƵĐƚŝŽŶďĞĐĂƵƐĞŽĨŝƚƐĞdžƚĞŶĚĞĚŚĂůĨͲůŝĨĞ͘,ŽǁĞǀĞƌ͕ĐŽŶĐĞŶƚƌĂƚŝŽŶƐ ŵŽŶŝƚŽƌŝŶŐĂůůŽǁĞĚƚŚĞĚĞƚĞĐƚŝŽŶŽĨĂƐĞǀĞƌĞƐŝƌŽůŝŵƵƐŽǀĞƌĚŽƐĂŐĞ͕ǁŝƚŚĂŵĂdžŝŵƵŵƚƌŽƵŐŚ ŵĞĂƐƵƌĞĚĂƚϱϵ͘ϯŶŐͬŵ>ŽŶĚĂLJϰĂĨƚĞƌƉŽƐĂĐŽŶĂnjŽůĞŝŶƚƌŽĚƵĐƚŝŽŶ͘WŽƐĂĐŽŶĂnjŽůĞƚƌŽƵŐŚ ĐŽŶĐĞŶƚƌĂƚŝŽŶǁĂƐŵĞĂƐƵƌĞĚĂƚϮ͘ϴϮђŐͬŵ>ŽŶƚŚĞƐĂŵĞďůŽŽĚƐĂŵƉůĞ͘^ŝƌŽůŝŵƵƐǁĂƐ ĚŝƐĐŽŶƚŝŶƵĞĚƵŶƚŝůĂĐŚŝĞǀĞŵĞŶƚŽĨƚŚĞƌĂƉĞƵƚŝĐƚƌŽƵŐŚĐŽŶĐĞŶƚƌĂƚŝŽŶĂŶĚǁĂƐƚŚĞƌĞĂĨƚĞƌ ƌĞŝŶƚƌŽĚƵĐĞĚĂƚƚŚĞĚŽƐĞŽĨϱŵŐƚǁŝĐĞĂǁĞĞŬ͕ĂŶĚƚŚĞŶƌĞĚƵĐĞĚƚŽϯŵŐƚǁŝĐĞĂǁĞĞŬ ;ĨŝŐƵƌĞϭͿ͘dŚĞƉŽƐĂĐŽŶĂnjŽůĞĚŽƐĞǁĂƐĂůƐŽƌĞĚƵĐĞĚƚŽϮϬϬŵŐYŽŶƚŚĞϭϰƚŚĚĂLJŽĨ ƚƌĞĂƚŵĞŶƚĂƐƚƌŽƵŐŚĐŽŶĐĞŶƚƌĂƚŝŽŶƐƌĞŵĂŝŶĞĚůĂƌŐĞůLJĂďŽǀĞƚŚĞƌĞĐŽŵŵĞŶĚĞĚƚĂƌŐĞƚϱ͘dŚĞ ƉĂƚŝĞŶƚĚŝĚŶŽƚĞdžƉĞƌŝĞŶĐĞĂŶLJĐůŝŶŝĐĂůůLJƌĞůĞǀĂŶƚĂĚǀĞƌƐĞĞǀĞŶƚƐŽƌďŝŽůŽŐŝĐĂůƉĞƌƚƵƌďĂƚŝŽŶƐ ĨŽůůŽǁŝŶŐƐŝƌŽůŝŵƵƐŽǀĞƌĚŽƐĂŐĞ͘ /ŶƚĞƌĂĐƚŝŽŶŵŽĚĞůďƵŝůĚŝŶŐ ůŽŽĚƐĂŵƉůĞƐŝƐƐƵĞĚĨƌŽŵƚŚĞƌŽƵƚŝŶĞĚƌƵŐŵŽŶŝƚŽƌŝŶŐŽĨƚŚŝƐƉĂƚŝĞŶƚǁĞƌĞƵƐĞĚƚŽŵĞĂƐƵƌĞ ƚƌŽƵŐŚĐŽŶĐĞŶƚƌĂƚŝŽŶƐŽĨƉŽƐĂĐŽŶĂnjŽůĞĂŶĚƐŝƌŽůŝŵƵƐǁŝƚŚĨƵůůLJǀĂůŝĚĂƚĞĚ>ͲD^D^ĂƐƐĂLJƐϲ͘ WŚĂƌŵĂĐŽŬŝŶĞƚŝĐŵŽĚĞůůŝŶŐǁĂƐƉĞƌĨŽƌŵĞĚƵƐŝŶŐDŽŶŽůŝdžϰ͘ϯ͘Ϯ͘;>ŝdžƐŽĨƚ͖KƌƐĂLJ͕&ƌĂŶĐĞͿ͘ƵĞ ƚŽƚŚĞŝƌĞŶŚĂŶĐĞĚďŝŽĂǀĂŝůĂďŝůŝƚLJ͕ƚŚĞƉŚĂƌŵĂĐŽŬŝŶĞƚŝĐƐŽĨƉŽƐĂĐŽŶĂnjŽůĞƚĂďůĞƚƐǁĂƐ ĞdžƉĞĐƚĞĚƚŽďĞŵƵĐŚĚŝĨĨĞƌĞŶƚƚŚĂŶƚŚĂƚŽĨƚŚĞŽƌĂůƐƵƐƉĞŶƐŝŽŶ͕ĂŶĚďĞĐĂƵƐĞŶŽ ĐŽŵƉĂƌƚŵĞŶƚĂůŵŽĚĞůŚĂƐďĞĞŶƉƵďůŝƐŚĞĚƚŽĚĂƚĞǁŝƚŚƉŽƐĂĐŽŶĂnjŽůĞƚĂďůĞƚƐ͕ƉŽƐĂĐŽŶĂnjŽůĞ

(6)

M

ANUS

C

R

IP

T

ACCEP

TED

WĂŐĞϱŽĨϭϯ ƉĂƌĂŵĞƚĞƌƐǁĞƌĞĞƐƚŝŵĂƚĞĚĚŝƌĞĐƚůLJĨƌŽŵƚŚĞŵĞĂƐƵƌĞĚĐŽŶĐĞŶƚƌĂƚŝŽŶƐ͘,ŽǁĞǀĞƌ͕ƚŚĞ ĂǀĂŝůĂďŝůŝƚLJŽĨƌĞƐŝĚƵĂůĐŽŶĐĞŶƚƌĂƚŝŽŶƐŽŶůLJĂŶĚƚŚĞǁŝĚĞŝŶƚƌĂͲŝŶĚŝǀŝĚƵĂůǀĂƌŝĂďŝůŝƚLJƌĞŶĚĞƌĞĚ ĚŝĨĨŝĐƵůƚƚŚĞĞƐƚŝŵĂƚŝŽŶ͘dŽĨĂĐŝůŝƚĂƚĞƚŚĞŵŽĚĞůůŝŶŐ͕ǁĞƉĞƌĨŽƌŵĞĚĂŐƌĂƉŚŝĐĂůĞdžƚƌĂĐƚŝŽŶŽĨ ƌŝĐŚƉŚĂƌŵĂĐŽŬŝŶĞƚŝĐƉƌŽĨŝůĞƐƌĞƉŽƌƚĞĚŝŶŚĞĂůƚŚLJǀŽůƵŶƚĞĞƌƐĂŶĚƚŚĞŵŽĚĞůǁĂƐďƵŝůƚĨƌŽŵ ƚŚĞƐĞĚĂƚĂŵĞƌŐĞĚǁŝƚŚƚŚŽƐĞŽĨƚŚĞƉĂƚŝĞŶƚϰ͘dŚĞŝŶĨůƵĞŶĐĞŽĨƚŚĞĐŽŶĚŝƚŝŽŶ;ŚĞĂůƚŚLJǀĞƌƐƵƐ ƉĂƚŝĞŶƚͿǁĂƐƚĞƐƚĞĚĂƐĂĐĂƚĞŐŽƌŝĐĂůĐŽǀĂƌŝĂƚĞŽĨƚŚĞƉĂƌĂŵĞƚĞƌƐƚŽĂĐĐŽƵŶƚĨŽƌƚŚĞ ĚŝĨĨĞƌĞŶĐĞƐďĞƚǁĞĞŶŚĞĂůƚŚLJǀŽůƵŶƚĞĞƌƐĂŶĚĂŐƌĂĨƚƌĞĐŝƉŝĞŶƚ͘ KŶĐĞƚŚĞƉĂƌĂŵĞƚĞƌƐŽĨƉŽƐĂĐŽŶĂnjŽůĞǁĞƌĞĐŽƌƌĞĐƚůLJĞƐƚŝŵĂƚĞĚ͕ĂĨƵůůĚĂƚĂƐĞƚĐŽŶƐŝƐƚŝŶŐŽĨ ƚŚĞƉĂƚŝĞŶƚ͛ƐƉŽƐĂĐŽŶĂnjŽůĞĂŶĚƐŝƌŽůŝŵƵƐĐŽŶĐĞŶƚƌĂƚŝŽŶƐǁĂƐďƵŝůƚ͘dŚĞƉŚĂƌŵĂĐŽŬŝŶĞƚŝĐ ƉĂƌĂŵĞƚĞƌƐŽĨƉŽƐĂĐŽŶĂnjŽůĞǁĞƌĞĨŝdžĞĚƚŽƚŚĞŝŶĚŝǀŝĚƵĂůǀĂůƵĞƐƉƌĞǀŝŽƵƐůLJĞƐƚŝŵĂƚĞĚƚŽ ĂǀŽŝĚĂďŝĂƐĞĚƌĞͲĞƐƚŝŵĂƚŝŽŶŽĨƚŚĞƉĂƌĂŵĞƚĞƌƐĚƵĞƚŽƚŚĞŝŵƉůĞŵĞŶƚĂƚŝŽŶŽĨƚŚĞŝŶƚĞƌĂĐƚŝŽŶ ŵŽĚĞů͘^ŝƌŽůŝŵƵƐƉĂƌĂŵĞƚĞƌƐǁĞƌĞĞƐƚŝŵĂƚĞĚĨƌŽŵĂƉƌĞǀŝŽƵƐůLJƉƵďůŝƐŚĞĚƉŚĂƌŵĂĐŽŬŝŶĞƚŝĐ ŵŽĚĞůŝŶŬŝĚŶĞLJƚƌĂŶƐƉůĂŶƚƌĞĐŝƉŝĞŶƚƐ͕ǁŝƚŚŽŶůLJƌĞƐŝĚƵĂůĞƌƌŽƌƉĂƌĂŵĞƚĞƌƐƌĞͲĞƐƚŝŵĂƚŝŽŶϳ͘ &ŽƌďŽƚŚŵŽĚĞůƐ͕ůŽŐͲŶŽƌŵĂůĚŝƐƚƌŝďƵƚŝŽŶŽĨƚŚĞƉĂƌĂŵĞƚĞƌƐǁĂƐĂƐƐƵŵĞĚ͘ dŚĞŝŶƚĞƌĂĐƚŝŽŶďĞƚǁĞĞŶƉŽƐĂĐŽŶĂnjŽůĞĂŶĚƐŝƌŽůŝŵƵƐǁĂƐŵŽĚĞůůĞĚďLJĂƉƉůLJŝŶŐĂŶŝŶŚŝďŝƚŝŽŶ ƚĞƌŵŽŶƐŝƌŽůŝŵƵƐĐůĞĂƌĂŶĐĞĂƐĨŽůůŽǁƐ͗ ܥܮௌூோ ൌ ܥܮ ή ൬ͳ െ ܫ݉ܽݔ ή ܥ௉ௌ௓ ܫܥͷͲ ൅ ܥ௉ௌ௓൰ tŚĞƌĞ>^/ZŝƐƚŚĞĂĐƚƵĂůĐůĞĂƌĂŶĐĞŽĨƐŝƌŽůŝŵƵƐ͕>ŝƐƚŚĞĐůĞĂƌĂŶĐĞŽĨƐŝƌŽůŝŵƵƐǁŝƚŚŽƵƚ ƉŽƐĂĐŽŶĂnjŽůĞ͕/ŵĂdžŝƐƚŚĞŵĂdžŝŵƵŵŝŶŚŝďŝƚŝŽŶŽĨƐŝƌŽůŝŵƵƐĐůĞĂƌĂŶĐĞ͕/ϱϬŝƐƚŚĞ ĐŽŶĐĞŶƚƌĂƚŝŽŶŽĨƉŽƐĂĐŽŶĂnjŽůĞƚŚĂƚŝŶŚŝďŝƚƐϱϬйŽĨƐŝƌŽůŝŵƵƐĐůĞĂƌĂŶĐĞ͕ĂŶĚW^ŝƐƚŚĞ ĐŽŶĐĞŶƚƌĂƚŝŽŶŽĨƉŽƐĂĐŽŶĂnjŽůĞ͘ ŽƐŝŶŐƐŝŵƵůĂƚŝŽŶƐ

(7)

M

ANUS

C

R

IP

T

ACCEP

TED

WĂŐĞϲŽĨϭϯ WŚĂƌŵĂĐŽŬŝŶĞƚŝĐƐŝŵƵůĂƚŝŽŶƐǁĞƌĞƉĞƌĨŽƌŵĞĚƚŽĞƐƚŝŵĂƚĞƚŚĞƉŚĂƌŵĂĐŽŬŝŶĞƚŝĐƉƌŽĨŝůĞƐŽĨ ƐŝƌŽůŝŵƵƐŝŶƚŚĞƉƌĞƐĞŶĐĞŽĨƉŽƐĂĐŽŶĂnjŽůĞǁŝƚŚĚŝĨĨĞƌĞŶƚĚŽƐŝŶŐƌĞŐŝŵĞŶƐ͘&ŽƌĞĂĐŚĚŽƐŝŶŐ ƌĞŐŝŵĞŶ͕ϱϬϬŝŶĚŝǀŝĚƵĂůƐǁĞƌĞƐŝŵƵůĂƚĞĚĂŶĚƚŚĞϱƚŚ͕ϮϱƚŚ͕ϳϱƚŚĂŶĚϵϱƚŚƉĞƌĐĞŶƚŝůĞƐǁĞƌĞ ĐĂůĐƵůĂƚĞĚ͘&ŽƌƚŚĞƉƵƌƉŽƐĞŽĨƚŚĞƐĞƐŝŵƵůĂƚŝŽŶƐ͕ƉŽƐĂĐŽŶĂnjŽůĞƉĂƌĂŵĞƚĞƌƐǁĞƌĞĨŝdžĞĚƐŽĂƐ ƚŽĂƉƉƌŽdžŝŵĂƚĞůLJƌĞĂĐŚƚŚĞƐƚĞĂĚLJƐƚĂƚĞĂĨƚĞƌƚŚĞƚǁŽůŽĂĚŝŶŐĚŽƐĞƐŽĨƚŚĞĨŝƌƐƚĚĂLJ͕ǁŝƚŚ ƚƌŽƵŐŚĐŽŶĐĞŶƚƌĂƚŝŽŶƐŽĨϮђŐͬŵ>͘ ZĞƐƵůƚƐ /ŶƚĞƌĂĐƚŝŽŶŵŽĚĞů ŽŶĞͲĐŽŵƉĂƌƚŵĞŶƚŵŽĚĞůǁŝƚŚĨŝƌƐƚŽƌĚĞƌĂďƐŽƌƉƚŝŽŶĂŶĚĞůŝŵŝŶĂƚŝŽŶĂŶĚƉƌŽƉŽƌƚŝŽŶĂů ƌĞƐŝĚƵĂůĞƌƌŽƌǁĂƐŝŵƉůĞŵĞŶƚĞĚƚŽĚĞƐĐƌŝďĞƉŽƐĂĐŽŶĂnjŽůĞƉŚĂƌŵĂĐŽŬŝŶĞƚŝĐƐ͘^ŝƌŽůŝŵƵƐ ĐŽŶĐĞŶƚƌĂƚŝŽŶƐǁĞƌĞǁĞůůĚĞƐĐƌŝďĞĚƵƐŝŶŐƚŚĞŵŽĚĞůƉƵďůŝƐŚĞĚďLJ>ƵŬĂƐĂŶĚĐŽůůĞĂŐƵĞƐ͕ ǁŚŝĐŚĨĞĂƚƵƌĞƐƐĞƋƵĞŶƚŝĂůƌůĂŶŐĂďƐŽƌƉƚŝŽŶĂŶĚĂƚǁŽͲĐŽŵƉĂƌƚŵĞŶƚƐƚƌƵĐƚƵƌĂůŵŽĚĞů ;ĨŝŐƵƌĞϭͿϳ͘,ŽǁĞǀĞƌ͕ƚŚŽƵŐŚƚŚĞLJƵƐĞĚĂŵŝdžĞĚĂĚĚŝƚŝǀĞͲƉƌŽƉŽƌƚŝŽŶĂůĞƌƌŽƌŵŽĚĞů͕ƚŚĞ ƉƌŽƉŽƌƚŝŽŶĂůĞƌƌŽƌƚĞƌŵǁĂƐƉŽŽƌůLJĞƐƚŝŵĂƚĞĚǁŝƚŚŽƵƌĚĂƚĂĂŶĚĂƐŝŵƉůĞĂĚĚŝƚŝǀĞƌĞƐŝĚƵĂů ĞƌƌŽƌŵŽĚĞůǁĂƐƵƐĞĚŝŶƐƚĞĂĚ͘dLJƉŝĐĂůĂŶĚŝŶĚŝǀŝĚƵĂůǀĂůƵĞƐŽĨƚŚĞƉĂƌĂŵĞƚĞƌƐĂƌĞƌĞƉŽƌƚĞĚ ŝŶƚĂďůĞϭ͘dŚĞǀĂůƵĞŽĨ/ŵĂdžǁĂƐĨŝdžĞĚƚŽϭĂĨƚĞƌƐĞǀĞƌĂůƌƵŶƐǁŝƚŚƐLJƐƚĞŵĂƚŝĐĂůĐŽŶǀĞƌŐĞŶĐĞ ƚŽƚŚŝƐǀĂůƵĞ͘dŚĞǀĂůƵĞŽĨƚŚĞ/ϱϬŽĨƉŽƐĂĐŽŶĂnjŽůĞĂŐĂŝŶƐƚƐŝƌŽůŝŵƵƐĐůĞĂƌĂŶĐĞǁĂƐ ĞƐƚŝŵĂƚĞĚĂƚϬ͘ϲϴђŐͬŵ>͘ůůƉĂƌĂŵĞƚĞƌƐǁĞƌĞĞƐƚŝŵĂƚĞĚǁŝƚŚŐŽŽĚĂĐĐƵƌĂĐLJ;ƚĂďůĞϭͿ͘ ŽƐŝŶŐƐŝŵƵůĂƚŝŽŶƐ ƐĞdžƉĞĐƚĞĚ͕ƚŚĞŵĂŝŶƚĞŶĂŶĐĞŽĨĂĚŽƐĞŽĨϱŵŐYŽĨƐŝƌŽůŝŵƵƐůĞĚƚŽŽǀĞƌĚŽƐĂŐĞŝŶĂůů ƐŝŵƵůĂƚĞĚƉĂƚŝĞŶƚƐ͘dŚĞŝŶƚĞƌͲŝŶĚŝǀŝĚƵĂůǀĂƌŝĂďŝůŝƚLJǁĂƐǀĞƌLJŝŵƉŽƌƚĂŶƚ͕ǁŝƚŚƚƌŽƵŐŚ ĐŽŶĐĞŶƚƌĂƚŝŽŶƐƌĂŶŐŝŶŐĨƌŽŵĂƌŽƵŶĚϭϱŶŐͬŵ>ĂƚƚŚĞϱƚŚƉĞƌĐĞŶƚŝůĞƵƉƚŽϭϯϬŶŐͬŵ>ĂƚƚŚĞ ϵϱƚŚƉĞƌĐĞŶƚŝůĞ͘dŚĞĚŽƐŝŶŐƐŝŵƵůĂƚŝŽŶƐƌĞǀĞĂůĞĚƚŚĂƚǁŝƚŚĂϱϬйĚŽƐĞƌĞĚƵĐƚŝŽŶ͕ƚŚĞƌĞǁĂƐ ŶŽƐŝŐŶŝĨŝĐĂŶƚĚĞĐƌĞĂƐĞŽĨƚŚĞĐŽŶĐĞŶƚƌĂƚŝŽŶƐĂŶĚĂůŵŽƐƚϵϬйŽĨŝŶĚŝǀŝĚƵĂůƐǁĞƌĞƐƚŝůůĂďŽǀĞ

(8)

M

ANUS

C

R

IP

T

ACCEP

TED

WĂŐĞϳŽĨϭϯ ƚŚĞƌĞĐŽŵŵĞŶĚĞĚƚŚĞƌĂƉĞƵƚŝĐƌĂŶŐĞŽĨϰͲϭϮŶŐͬŵ>ŽĨƚƌŽƵŐŚƐŝƌŽůŝŵƵƐ͘ϴϬйĚĞĐƌĞĂƐĞ ĨƌŽŵϱŵŐYƚŽϭŵŐYĂůůŽǁĞĚĂƌŽƵŶĚĂƚŚŝƌĚŽĨƚŚĞƐŝŵƵůĂƚĞĚƉĂƚŝĞŶƚƐƚŽƌĞĂĐŚƚŚĞ ƚŚĞƌĂƉĞƵƚŝĐƌĂŶŐĞ͕ĂƐǁĞůůĂƐĚŝĚĂŶĂĚĂƉƚĞĚƌĞŐŝŵĞŶŽĨϯŵŐĞǀĞƌLJƚŚƌĞĞĚĂLJƐ͘,ŽǁĞǀĞƌ͕ ƚŚĞƐĞƚǁŽƌĞŐŝŵĞŶƐĚŝĨĨĞƌĞĚŽŶƚŚĞǀĂůƵĞƐŽĨƚƌŽƵŐŚĐŽŶĐĞŶƚƌĂƚŝŽŶƐǁŚŝĐŚǁĞƌĞŚŝŐŚĞƌǁŝƚŚ ϭŵŐY͕ǁŚĞƌĞĂƐƚŚŽƐĞŽďƚĂŝŶĞĚǁŝƚŚϯŵŐĞǀĞƌLJƚŚƌĞĞĚĂLJƐǁĞƌĞĐůŽƐĞƚŽƐƚĂŶĚĂƌĚ ƚƌĞĂƚŵĞŶƚǁŝƚŚŽƵƚƉŽƐĂĐŽŶĂnjŽůĞ͘^ŝŵŝůĂƌůLJ͕ƚŚĞǀĂůƵĞƐŽĨƚŚĞŵĂdžŝŵƵŵĐŽŶĐĞŶƚƌĂƚŝŽŶƐǁĞƌĞ ǀĞƌLJůŽǁǁŝƚŚϭŵŐYǁŚĞƌĞĂƐƉĞĂŬĐŽŶĐĞŶƚƌĂƚŝŽŶƐǁŝƚŚϯŵŐĞǀĞƌLJƚŚƌĞĞĚĂLJƐǁĞƌĞĐůŽƐĞ ƚŽƚŚŽƐĞŽďƚĂŝŶĞĚǁŝƚŚƚŚĞƐƚĂŶĚĂƌĚƚƌĞĂƚŵĞŶƚǁŝƚŚŽƵƚƉŽƐĂĐŽŶĂnjŽůĞ;ĨŝŐƵƌĞϮͿ͘ ŝƐĐƵƐƐŝŽŶ ĂƐĞĚŽŶĂĐĂƐĞŽĨĚƌƵŐͲĚƌƵŐŝŶƚĞƌĂĐƚŝŽŶ͕ǁĞĞƐƚĂďůŝƐŚĞĚĂƉŚĂƌŵĂĐŽŬŝŶĞƚŝĐŵŽĚĞůƚŽ ĚĞƐĐƌŝďĞƚŚĞŝŶŚŝďŝƚŝŽŶŽĨƐŝƌŽůŝŵƵƐĐůĞĂƌĂŶĐĞďLJƉŽƐĂĐŽŶĂnjŽůĞ͘dŚĞĐŽŶĐĞŶƚƌĂƚŝŽŶͲƚŝŵĞ ƉƌŽĨŝůĞŽĨƐŝƌŽůŝŵƵƐŽĨƚŚĞƉĂƚŝĞŶƚŝŶĂďƐĞŶĐĞŽĨƉŽƐĂĐŽŶĂnjŽůĞǁĂƐĐŽŵƉĂƌĂďůĞƚŽǁŚĂƚǁĂƐ ƉƌĞǀŝŽƵƐůLJƌĞƉŽƌƚĞĚŝŶŬŝĚŶĞLJƚƌĂŶƐƉůĂŶƚƌĞĐŝƉŝĞŶƚƐϳ͘^ŝŵŝůĂƌůLJ͕ƚŚĞƚƌŽƵŐŚĐŽŶĐĞŶƚƌĂƚŝŽŶƐŽĨ ƉŽƐĂĐŽŶĂnjŽůĞǁŚĞƌĞǁŝƚŚŝŶƚŚĞƌĂŶŐĞƌĞƉŽƌƚĞĚŝŶƐƚĞŵĐĞůůƚƌĂŶƐƉůĂŶƚƌĞĐŝƉŝĞŶƚƐƚƌĞĂƚĞĚ ǁŝƚŚƉŽƐĂĐŽŶĂnjŽůĞƚĂďůĞƚƐϯϬϬŵŐYϴ͘ĐůĂƐƐŝĐĂůŝŶŚŝďŝƚŝŽŶŵŽĚĞůĂůůŽǁĞĚƚŽĚĞƐĐƌŝďĞǁĞůů ƚŚĞŝŶƚĞƌĂĐƚŝŽŶ͘dŚĞǀĂůƵĞŽĨƚŚĞ/ϱϬǁĞĞƐƚŝŵĂƚĞĚǁĂƐĐůŽƐĞƚŽƚŚĂƚƌĞƉŽƌƚĞĚŝŶŝŶͲǀŝƚƌŽ ƐƚƵĚŝĞƐ;Ϭ͘ϵϭђŐͬŵ>Ϳ͕ǁŚŝĐŚĐŽŵĨŽƌƚƐŽƵƌƌĞƐƵůƚƐϵ͘ dŚĞĂĐĐƵŵƵůĂƚŝŽŶŽĨƐŝƌŽůŝŵƵƐŽĐĐƵƌƌĞĚƌĂƉŝĚůLJĂĨƚĞƌƉŽƐĂĐŽŶĂnjŽůĞǁĂƐƐƚĂƌƚĞĚ͕ƐŝƌŽůŝŵƵƐ ƚƌŽƵŐŚĐŽŶĐĞŶƚƌĂƚŝŽŶďĞŝŶŐŝŶĐƌĞĂƐĞĚďLJϱ͘ϳĨŽůĚĂĨƚĞƌŽŶůLJϮĚĂLJƐŽĨƚƌĞĂƚŵĞŶƚ͘dŚĞ ĐŽŶĐĞŶƚƌĂƚŝŽŶͬĚŽƐĞƌĂƚŝŽǁĂƐŝŶĐƌĞĂƐĞĚďLJϴ͘ϱĨŽůĚŽŶĚĂLJϰ͕ǁŚŝĐŚŝƐŵƵĐŚŵŽƌĞƚŚĂŶ ƉƌĞǀŝŽƵƐůLJƌĞƉŽƌƚĞĚǁŝƚŚƚŚĞŽƌĂůƐƵƐƉĞŶƐŝŽŶϭ͘dŚŝƐĚĞŵŽŶƐƚƌĂƚĞƐĂĨĂƐƚĂƚƚĂŝŶŵĞŶƚŽĨƚŚĞ ĐŽŶĐĞŶƚƌĂƚŝŽŶƚŚƌĞƐŚŽůĚĨŽƌĂŶĞĨĨĞĐƚŝǀĞďůŽĐŬĂĚĞŽĨƐŝƌŽůŝŵƵƐŵĞƚĂďŽůŝƐŵďLJzWϯϰǁŚŝĐŚ ĐĂŶďĞĂƚƚƌŝďƵƚĞĚƚŽƚŚĞƵƐĞŽĨĂůŽĂĚŝŶŐĚŽƐĞƚŽŐĞƚŚĞƌǁŝƚŚĞŶŚĂŶĐĞĚďŝŽĂǀĂŝůĂďŝůŝƚLJŽĨ ƉŽƐĂĐŽŶĂnjŽůĞƚĂďůĞƚƐĂƐĐŽŵƉĂƌĞĚǁŝƚŚƚŚĞŽƌĂůƐƵƐƉĞŶƐŝŽŶ͘dŚĞƉŚĂƌŵĂĐŽŬŝŶĞƚŝĐ

(9)

M

ANUS

C

R

IP

T

ACCEP

TED

WĂŐĞϴŽĨϭϯ ƐŝŵƵůĂƚŝŽŶƐǁĞƉĞƌĨŽƌŵĞĚƵƐŝŶŐƚŚĞŝŶƚĞƌĂĐƚŝŽŶŵŽĚĞůƐƵŐŐĞƐƚĞĚƚŚĂƚĐƵƌƌĞŶƚ ƌĞĐŽŵŵĞŶĚĂƚŝŽŶƐƌĞŐĂƌĚŝŶŐĚŽƐĞƌĞĚƵĐƚŝŽŶǁŝƚŚƉŽƐĂĐŽŶĂnjŽůĞŵĂLJŶŽƚďĞƐƵŝƚĂďůĞƚŽƚŚĞ ƵƐĞŽĨƚŚĞŶĞǁƉŽƐĂĐŽŶĂnjŽůĞƚĂďůĞƚĨŽƌŵƵůĂƚŝŽŶ͕ĚƵĞƚŽƚŚŝƐĞŶŚĂŶĐĞĚďŝŽĂǀĂŝůĂďŝůŝƚLJůĞĂĚŝŶŐ ƚŽŚŝŐŚĞƌĐŽŶĐĞŶƚƌĂƚŝŽŶƐ͘ ƐĂƌĞƐƵůƚŽĨƚŚŝƐŝŶĐƌĞĂƐĞĚďŝŽĂǀĂŝůĂďŝůŝƚLJ͕ƚŚĞĞƐƚŝŵĂƚĞĚǀĂůƵĞƐŽĨsͬ&ĂŶĚ>ͬ&ŽĨ ƉŽƐĂĐŽŶĂnjŽůĞǁĞƌĞŶŽƚŝĐĞĂďůLJůŽǁĞƌƚŚĂŶƚŚŽƐĞƌĞƉŽƌƚĞĚďĞĨŽƌĞŝŶĐŽŵƉĂƌƚŵĞŶƚĂůƐƚƵĚŝĞƐ͘ ,ŽǁĞǀĞƌ͕ŽƵƌĚĂƚĂƐŚŽǁƚŚĂƚĚĞƐƉŝƚĞƚŚĞŝŵƉƌŽǀĞŵĞŶƚŽĨƉŽƐĂĐŽŶĂnjŽůĞďŝŽĂǀĂŝůĂďŝůŝƚLJ͕ĂŶ ŝŵƉŽƌƚĂŶƚŝŶƚƌĂͲŝŶĚŝǀŝĚƵĂůǀĂƌŝĂďŝůŝƚLJƌĞŵĂŝŶƐ͕ǁŚŝĐŚŚĂƐŶŽƚďĞĞŶĞdžƉůŽƌĞĚƚŽĚĂƚĞ͘dŚŝƐ ǁŝĚĞŝŶƚƌĂͲŝŶĚŝǀŝĚƵĂůǀĂƌŝĂďŝůŝƚLJǁĂƐƉŽŽƌůLJĚĞƐĐƌŝďĞĚďLJƚŚĞƉŚĂƌŵĂĐŽŬŝŶĞƚŝĐŵŽĚĞůďĞĐĂƵƐĞ ŽŶůLJŽŶĞĐŽŶĐĞŶƚƌĂƚŝŽŶƉĞƌǁĞĞŬǁĂƐĂǀĂŝůĂďůĞ͕ĂŶĚƚŚĞƌĞĨŽƌĞǁĂƐŶŽƚƌĞƚĂŝŶĚŝŶƚŚĞĨŝŶĂů ŵŽĚĞů͘,ŽǁĞǀĞƌ͕ƚŚĞĐŽŶĐĞŶƚƌĂƚŝŽŶƐŽĨƐŝƌŽůŝŵƵƐǁĞƌĞǁĞůůƉƌĞĚŝĐƚĞĚƵƐŝŶŐĂŶĂǀĞƌĂŐĞ ĐŽŶĐĞŶƚƌĂƚŝŽŶͲƚŝŵĞƉƌŽĨŝůĞŽĨƉŽƐĂĐŽŶĂnjŽůĞ͕ǁŚŝĐŚŝŶĚŝĐĂƚĞƐƚŚĂƚŽƵƌŵŽĚĞůĚĞƐĐƌŝďĞƐǁĞůů ƚŚĞĞǀŽůƵƚŝŽŶŽĨƚŚĞĐůĞĂƌĂŶĐĞŽĨƐŝƌŽůŝŵƵƐ͘dŚĞĂĚĚŝƚŝŽŶŽĨĂŶŝŶƚĞƌͲŽĐĐĂƐŝŽŶǀĂƌŝĂďŝůŝƚLJŽĨ ƚŚĞĂďƐŽƌƉƚŝŽŶŽĨƉŽƐĂĐŽŶĂnjŽůĞĂůůŽǁĞĚƚŽƌĞĨŝŶĞƚŚĞƉƌĞĚŝĐƚŝŽŶŽĨŝƚƐĐŽŶĐĞŶƚƌĂƚŝŽŶƐ͕ďƵƚ ƚŚĞƌĞƐƵůƚŝŶŐŝŵƉƌŽǀĞŵĞŶƚŽĨƐŝƌŽůŝŵƵƐĨŝƚƚŝŶŐǁĂƐŵŽĚĞƐƚĂŶĚƚŚƵƐƚŚĞƐŝŵƉůĞƐƚŵŽĚĞůǁĂƐ ƉƌĞĨĞƌƌĞĚ͘/ŶĂĚĚŝƚŝŽŶ͕ƚŚĞƉŚĂƌŵĂĐŽŬŝŶĞƚŝĐƉĂƌĂŵĞƚĞƌƐŽĨƉŽƐĂĐŽŶĂnjŽůĞǁĞƌĞĞƐƚŝŵĂƚĞĚ ŝŶĚĞƉĞŶĚĞŶƚůLJŽĨƚŚĞŝŶƚĞƌĂĐƚŝŽŶŵŽĚĞůďƵŝůĚŝŶŐ͕ĂŶĚĂƌĞƚŚƵƐďĞůŝĞǀĞĚƚŽďĞĂƐƐƚƌŽŶŐůLJ ĞƐƚŝŵĂƚĞĚĂƐƉŽƐƐŝďůĞǁŝƚŚƚŚĞĂǀĂŝůĂďůĞĚĂƚĂ͘DŽƌĞŽǀĞƌ͕ƚŚĞǀĂůƵĞŽĨƚŚĞ/ϱϬǁĂƐĨĂƌďĞůŽǁ ƚŚĞŵĞĂƐƵƌĞĚƚƌŽƵŐŚĐŽŶĐĞŶƚƌĂƚŝŽŶƐŽĨƉŽƐĂĐŽŶĂnjŽůĞ͕ĂŶĚƚŚƵƐƚŚĞůĞǀĞůŽĨŝŶŚŝďŝƚŝŽŶǁĂƐ ĐůŽƐĞƚŽƚŚĞŵĂdžŝŵƵŵŽǀĞƌĂůůƚŚĞŽďƐĞƌǀĂƚŝŽŶƉĞƌŝŽĚ͘džĐĞƉƚŵĂĚĞŽĨŽŶĞĐŽŶĐĞŶƚƌĂƚŝŽŶ͕ ƚŚĞŝŶŚŝďŝƚŝŽŶůĞǀĞůĂƚƚŚĞƚŝŵĞŽĨƚŚĞƚƌŽƵŐŚůĞǀĞůƌĂŶŐĞĚďĞƚǁĞĞŶϳϭйĂŶĚϴϱй͘dŚĞŽŶůLJ ůŽǁƚƌŽƵŐŚĐŽŶĐĞŶƚƌĂƚŝŽŶŽĨƉŽƐĂĐŽŶĂnjŽůĞ͕ŵĞĂƐƵƌĞĚĂƚϬ͘ϯϭђŐͬŵ>͕ǁĂƐůĂƌŐĞůLJ ŽǀĞƌĞƐƚŝŵĂƚĞĚǁŚŝĐŚƌĞƐƵůƚĞĚŝŶĂŶƵŶĚĞƌĞƐƚŝŵĂƚŝŽŶŽĨƐŝƌŽůŝŵƵƐĐůĞĂƌĂŶĐĞĂŶĚĂŶ ŽǀĞƌĞƐƚŝŵĂƚŝŽŶŽĨƚŚĞƉƌĞĚŝĐƚĞĚĐŽŶĐĞŶƚƌĂƚŝŽŶŽĨƐŝƌŽůŝŵƵƐ;ĨŝŐƵƌĞϭͿ͘

(10)

M

ANUS

C

R

IP

T

ACCEP

TED

WĂŐĞϵŽĨϭϯ ŽŶĐůƵƐŝŽŶ dŚŽƵŐŚĐŽŶĐůƵƐŝŽŶƐĐĂŶŶŽƚďĞĚƌĂǁŶĨƌŽŵĂƐŝŶŐůĞŽďƐĞƌǀĂƚŝŽŶ͕ƚŚĞƌĞƐƵůƚƐŽĨƚŚĞ ƐŝŵƵůĂƚŝŽŶƐƐƵŐŐĞƐƚƚŚĂƚĐƵƌƌĞŶƚƌĞĐŽŵŵĞŶĚĂƚŝŽŶƐŽĨĚŽƐĞƌĞĚƵĐƚŝŽŶĨŽƌƚŚĞŽƌĂůƐƵƐƉĞŶƐŝŽŶ ŽĨƉŽƐĂĐŽŶĂnjŽůĞŵŝŐŚƚďĞŝŶƐƵĨĨŝĐŝĞŶƚǁŝƚŚƚŚĞƚĂďůĞƚĨŽƌŵƵůĂƚŝŽŶ͘/ĨƚŚĞƵƐĞŽĨƉŽƐĂĐŽŶĂnjŽůĞ ĐĂŶŶŽƚďĞĂǀŽŝĚĞĚ͕ƐŝƌŽůŝŵƵƐĚŽƐĞƐƐŚŽƵůĚďĞƌĞĚƵĐĞĚĂƐƐŽŽŶĂƐƉŽƐĂĐŽŶĂnjŽůĞŝƐƐƚĂƌƚĞĚ͘ ϰϬйĚŽƐĞƌĞĚƵĐƚŝŽŶĂĚŵŝŶŝƐƚĞƌĞĚĞǀĞƌLJϯĚĂLJƐŵĂLJďĞƐƵŝƚĂďůĞ͘dŚĞǀĞƌLJŚŝŐŚ ĐŽŶĐĞŶƚƌĂƚŝŽŶƐŽďƚĂŝŶĞĚŝŶĐĞƌƚĂŝŶƉĂƚŝĞŶƚƐĂůƐŽƌŝƐĞƐƚŚĞƋƵĞƐƚŝŽŶƐŽĨƚŚĞƌĞĚƵĐƚŝŽŶŽĨ ƉŽƐĂĐŽŶĂnjŽůĞĚŽƐĞƐŝŶĚĞƉĞŶĚĞŶƚůLJŽĨƚŽůĞƌĂŶĐĞŝƐƐƵĞƐ͘ĐůŽƐĞĐŽŶĐĞŶƚƌĂƚŝŽŶŵŽŶŝƚŽƌŝŶŐŝƐ ŚŝŐŚůLJƌĞĐŽŵŵĞŶĚĞĚĨƌŽŵƉŽƐĂĐŽŶĂnjŽůĞŝŶŝƚŝĂƚŝŽŶƚŽƐƚĞĂĚLJͲƐƚĂƚĞĂĐŚŝĞǀĞŵĞŶƚ͕ĂŶĚƚŚĞŶĂƚ ůĞĂƐƚϳĚĂLJƐĂĨƚĞƌƉŽƐĂĐŽŶĂnjŽůĞĚŝƐĐŽŶƚŝŶƵĂƚŝŽŶŐŝǀĞŶŝƚƐĞdžƚĞŶĚĞĚŚĂůĨͲůŝĨĞ͘ůƐŽ͕ŐŝǀĞŶƚŚĞ ŝŶƚĞƌĂĐƚŝŽŶƉŽƚĞŶƚŝĂůŽĨƚŚŝƐŶĞǁĨŽƌŵƵůĂƚŝŽŶ͕ƚŚĞƌĞŝƐĂŶƵƌŐĞŶƚŶĞĞĚƚŽƵŶĚĞƌƚĂŬĞ͞ƌĞĂůͲůŝĨĞ ĐŽŶĚŝƚŝŽŶƐ͟ƐƚƵĚŝĞƐƚŽĞdžƉůŽƌĞƚŚĞƐŽƵƌĐĞƐŽĨƉŚĂƌŵĂĐŽŬŝŶĞƚŝĐŝŶƚĞƌĂŶĚŝŶƚƌĂͲŝŶĚŝǀŝĚƵĂů ǀĂƌŝĂďŝůŝƚLJŽĨƉŽƐĂĐŽŶĂnjŽůĞĂĚŵŝŶŝƐƚĞƌĞĚĂƐƚĂďůĞƚƐ͘  

(11)

M

ANUS

C

R

IP

T

ACCEP

TED

WĂŐĞϭϬŽĨϭϯ

ŝƐĐůŽƐƵƌĞƐ

dŚĞĂƵƚŚŽƌƐŚĂǀĞŶŽƚŚŝŶŐƚŽĚŝƐĐůŽƐĞ͘

ŬŶŽǁůĞĚŐĞŵĞŶƚƐ

dŚĞĂƵƚŚŽƌƐǁŝƐŚƚŽƚŚĂŶŬƌ͘'͘ĞƐůĂŶĚĞƐĨŽƌŚŝƐƚĞĐŚŶŝĐĂůƐƵƉƉŽƌƚ͘





(12)

M

ANUS

C

R

IP

T

ACCEP

TED

WĂŐĞϭϭŽĨϭϯ

ZĞĨĞƌĞŶĐĞƐ

 ϭ͘ ŚŽ ͕ ŚĂŶ ,͕ EŐƵLJĞŶ ,D͕ Ğƚ Ăů͘ DĂŶĂŐĞŵĞŶƚ ŽĨ ĚƌƵŐ ŝŶƚĞƌĂĐƚŝŽŶ ďĞƚǁĞĞŶ ƉŽƐĂĐŽŶĂnjŽůĞ ĂŶĚ ƐŝƌŽůŝŵƵƐ ŝŶ ƉĂƚŝĞŶƚƐ ǁŚŽ ƵŶĚĞƌŐŽ ŚĞŵĂƚŽƉŽŝĞƚŝĐ ƐƚĞŵ ĐĞůů ƚƌĂŶƐƉůĂŶƚ͘WŚĂƌŵĂĐŽƚŚĞƌĂƉLJ͘ϮϬϭϱ͖ϯϱ;ϲͿ͗ϱϳϴͲϱϴϱ͘ĚŽŝ͗ϭϬ͘ϭϬϬϮͬƉŚĂƌ͘ϭϲϬϬ͘ Ϯ͘ DŽƚŽŶ͕DĂ>͕<ƌŝƐŚŶĂ'͕ĞƚĂů͘ĨĨĞĐƚƐŽĨŽƌĂůƉŽƐĂĐŽŶĂnjŽůĞŽŶƚŚĞƉŚĂƌŵĂĐŽŬŝŶĞƚŝĐƐ ŽĨ ƐŝƌŽůŝŵƵƐ͘ Ƶƌƌ DĞĚ ZĞƐ KƉŝŶ͘ ϮϬϬϵ͖Ϯϱ;ϯͿ͗ϳϬϭͲϳϬϳ͘ ĚŽŝ͗ ϭϬ͘ϭϭϴϱͬϬϯϬϬϳϵϵϬϴϬϮϲϰϰϮϬϵ͘ ϯ͘ WĞŬƐĂ '͕ ^ĐŚƵůƚnj <͕ &ƵŶŐ ,͘ ŽƐŝŶŐ ĂůŐŽƌŝƚŚŵ ĨŽƌ ĐŽŶĐŽŵŝƚĂŶƚ ĂĚŵŝŶŝƐƚƌĂƚŝŽŶ ŽĨ ƐŝƌŽůŝŵƵƐ͕ ƚĂĐƌŽůŝŵƵƐ͕ ĂŶĚ ĂŶ ĂnjŽůĞ ĂĨƚĞƌ ĂůůŽŐĞŶĞŝĐ ŚĞŵĂƚŽƉŽŝĞƚŝĐ ƐƚĞŵ ĐĞůů ƚƌĂŶƐƉůĂŶƚĂƚŝŽŶ͘ : KŶĐŽů WŚĂƌŵ WƌĂĐƚ͘ ϮϬϭϱ͖Ϯϭ;ϲͿ͗ϰϬϵͲϰϭϱ͘ ĚŽŝ͗ ϭϬ͘ϭϭϳϳͬϭϬϳϴϭϱϱϮϭϰϱϯϵϴϮϱ͘ ϰ͘ <ƌŝƐŚŶĂ '͕ DĂ >͕ DĂƌƚŝŶŚŽ D͕ Ğƚ Ăů͘  ŶĞǁ ƐŽůŝĚ ŽƌĂů ƚĂďůĞƚ ĨŽƌŵƵůĂƚŝŽŶ ŽĨ ƉŽƐĂĐŽŶĂnjŽůĞ͗ Ă ƌĂŶĚŽŵŝnjĞĚ ĐůŝŶŝĐĂů ƚƌŝĂů ƚŽ ŝŶǀĞƐƚŝŐĂƚĞ ƌŝƐŝŶŐ ƐŝŶŐůĞͲ ĂŶĚ ŵƵůƚŝƉůĞͲ ĚŽƐĞ ƉŚĂƌŵĂĐŽŬŝŶĞƚŝĐƐ ĂŶĚ ƐĂĨĞƚLJ ŝŶ ŚĞĂůƚŚLJ ǀŽůƵŶƚĞĞƌƐ͘ : ŶƚŝŵŝĐƌŽď ŚĞŵŽƚŚĞƌ͘ ϮϬϭϮ͖ϲϳ;ϭϭͿ͗ϮϳϮϱͲϮϳϯϬ͘ĚŽŝ͗ϭϬ͘ϭϬϵϯͬũĂĐͬĚŬƐϮϲϴ͘ ϱ͘ />͘ ĐĐĞƐƐĞĚ ĂƉƌŝů ϮϬϭϲ͘ ǁǁǁ͘ŬŽďĞ͘ĨƌͬĞĐŝůͬƚĞůĞĐŚĂƌŐĞŵĞŶƚƐϮϬϭϱͬ/>ϲͲdƌŝĂnjŽůĞͲ dDͲϬϳͲϭϮͲϮϬϭϱͲ>ĞǁŝƐͲZͲĞƚͲĂů͘ƉĚĨ͘ ϲ͘ sĞƌĚŝĞƌ D͕ ĞŶƚƵĞͲ&ĞƌƌĞƌ ͕ dƌŝďƵƚ K͕ Ğƚ Ăů͘ >ŝƋƵŝĚ ĐŚƌŽŵĂƚŽŐƌĂƉŚLJͲƚĂŶĚĞŵ ŵĂƐƐ ƐƉĞĐƚƌŽŵĞƚƌLJ ŵĞƚŚŽĚ ĨŽƌ ƐŝŵƵůƚĂŶĞŽƵƐ ƋƵĂŶƚŝĨŝĐĂƚŝŽŶ ŽĨ ĨŽƵƌ ƚƌŝĂnjŽůĞ ĂŶƚŝĨƵŶŐĂů ĂŐĞŶƚƐ ŝŶ ŚƵŵĂŶ ƉůĂƐŵĂ͘ ůŝŶ ŚĞŵ >Ăď DĞĚ͘ ϮϬϭϬ͖ϰϴ;ϭϬͿ͗ϭϱϭϱͲϭϱϮϮ͘ ĚŽŝ͗ ϭϬ͘ϭϱϭϱͬ>D͘ϮϬϭϬ͘ϮϱϮ͘ ϳ͘ >ƵŬĂƐ :͕ ĂůǀŽ Z͕ ŽŐƌĂĨŝĚŝƐ ͕ Ğƚ Ăů͘ ^ŝŵƵůĂƚŝŽŶ ŽĨ ƐŝƌŽůŝŵƵƐ ĞdžƉŽƐƵƌĞƐ ĂŶĚ ƉŽƉƵůĂƚŝŽŶ ǀĂƌŝĂďŝůŝƚLJ ŝŵŵĞĚŝĂƚĞůLJ ƉŽƐƚ ƌĞŶĂů ƚƌĂŶƐƉůĂŶƚĂƚŝŽŶ͗ ŝŵƉŽƌƚĂŶĐĞ ŽĨ ƚŚĞ ƉĂƚŝĞŶƚΖƐzWϯϱŐĞŶŽƚLJƉĞŝŶƚĂŝůŽƌŝŶŐƚƌĞĂƚŵĞŶƚ͘ŝŽƉŚĂƌŵƌƵŐŝƐƉŽƐ͘ϮϬϭϬ͖ϯϭ;ϮͲ ϯͿ͗ϭϮϵͲϭϯϳ͘ĚŽŝ͗ϭϬ͘ϭϬϬϮͬďĚĚ͘ϲϵϳ͘ ϴ͘ ŽƌŶĞůLJK͕ƵĂƌƚĞZ&͕,ĂŝĚĞƌ^͕ĞƚĂů͘WŚĂƐĞϯƉŚĂƌŵĂĐŽŬŝŶĞƚŝĐƐĂŶĚƐĂĨĞƚLJƐƚƵĚLJŽĨ Ă ƉŽƐĂĐŽŶĂnjŽůĞ ƚĂďůĞƚ ĨŽƌŵƵůĂƚŝŽŶ ŝŶ ƉĂƚŝĞŶƚƐ Ăƚ ƌŝƐŬ ĨŽƌ ŝŶǀĂƐŝǀĞ ĨƵŶŐĂů ĚŝƐĞĂƐĞ͘ : ŶƚŝŵŝĐƌŽďŚĞŵŽƚŚĞƌ͘ϮϬϭϱ͖ϭϬ͘ϭϬϵϯͬũĂĐͬĚŬǀϯϴϬ͘ĚŽŝ͗ϭϬ͘ϭϬϵϯͬũĂĐͬĚŬǀϯϴϬ͘ ϵ͘ tĞdžůĞƌ͕ŽƵƌƚŶĞLJZ͕ZŝĐŚĂƌĚƐt͕ĞƚĂů͘ĨĨĞĐƚŽĨƉŽƐĂĐŽŶĂnjŽůĞŽŶĐLJƚŽĐŚƌŽŵĞWϰϱϬ ĞŶnjLJŵĞƐ͗ Ă ƌĂŶĚŽŵŝnjĞĚ͕ ŽƉĞŶͲůĂďĞů͕ ƚǁŽͲǁĂLJ ĐƌŽƐƐŽǀĞƌ ƐƚƵĚLJ͘ Ƶƌ : WŚĂƌŵ ^Đŝ͘ ϮϬϬϰ͖Ϯϭ;ϱͿ͗ϲϰϱͲϲϱϯ͘ĚŽŝ͗ϭϬ͘ϭϬϭϲͬũ͘ĞũƉƐ͘ϮϬϬϰ͘Ϭϭ͘ϬϬϱ͘  

(13)

M

ANUS

C

R

IP

T

ACCEP

TED

WĂŐĞϭϮŽĨϭϯ dĂďůĞ dĂďůĞϭ͘WĂƌĂŵĞƚĞƌǀĂůƵĞƐŝŶƚŚĞĨŝŶĂůŵŽĚĞů      ^ŝƌŽůŝŵƵƐϳ    WŽƐĂĐŽŶĂnjŽůĞ    WĂƌĂŵĞƚĞƌ ƐƚŝŵĂƚĞ Z^ /ŶĚŝǀŝĚƵĂů ƐƚŝŵĂƚĞ WĂƌĂŵĞƚĞƌ ƐƚŝŵĂƚĞ Z^ /ŶĚŝǀŝĚƵĂů ƐƚŝŵĂƚĞ &ŝdžĞĚĞĨĨĞĐƚƐ &ŝdžĞĚĞĨĨĞĐƚƐ Ŭƚƌ;ŚͲϭͿ ϱ͘Ϯϲ ĨŝdžĞĚ ϱ͘ϳϯ ŬĂ;ŚͲϭͿ Ϭ͘ϬϯϬϮ ϰ Ϭ͘ϬϭϬϳ sϭ;>Ϳ Ϯϭϵ ĨŝdžĞĚ ϭϭϴ β ŬĂ Ͳϭ͘Ϭϰ Ϯϯ Eͬ >;>͘ŚͲϭͿ ϭϱ͘ϵ ĨŝdžĞĚ ϵ͘ϱϱ sϭ;>Ϳ ϭϰ͘ϵ ϭϰ ϭϰ͘ϵ sϮ;>Ϳ Ϯϳϯ ĨŝdžĞĚ ϰϬϰ >;>͘ŚͲϭͿ ϲ͘ϵϭ ϭϴ ϯ͘Ϯ Y;>͘ŚͲϭͿ ϯϴ͘Ϯ ĨŝdžĞĚ ϯϴ͘Ϯ /ϱϬ;ђŐ͘ŵ>ͲϭͿ Ϭ͘ϲϴϭ ϭ Ϭ͘ϲϴϭ /ŵĂdž ϭ ĨŝdžĞĚ ϭ ZĂŶĚŽŵĞĨĨĞĐƚƐ ^sŽŶŬƚƌ;йͿ Ϭ͘ϰϯ ĨŝdžĞĚ Eͬ ZĂŶĚŽŵĞĨĨĞĐƚƐ ^sŽŶsϭ;йͿ Ϭ͘ϱϯ ĨŝdžĞĚ Eͬ ^sŽŶ>;йͿ Ϭ͘ϰϬ ϯϯ Eͬ ^sŽŶ>;йͿ Ϭ͘ϱϴ ĨŝdžĞĚ Eͬ ^sŽŶsϮ;йͿ Ϭ͘ϳϱ ĨŝdžĞĚ Eͬ ƌƌŽƌŵŽĚĞů ^sŽŶY;йͿ Ϭ͘ϭϮ ĨŝdžĞĚ Eͬ WƌŽƉŽƌƚŝŽŶĂů ĞƌƌŽƌ;йͿ Ϭ͘ϯϰ Ϯϭ Eͬ ƌƌŽƌŵŽĚĞů ĚĚŝƚŝǀĞĞƌƌŽƌ ;ŶŐ͘ŵ>ͲϭͿ Ϯ͘Ϭϯ ϮϮ Eͬ          Z^͗ZĞůĂƚŝǀĞ^ƚĂŶĚĂƌĚƌƌŽƌ͘^s͗ĞƚǁĞĞŶ^ƵďũĞĐƚsĂƌŝĂďŝůŝƚLJ͘βŬĂƋƵĂŶƚŝĨŝĞƐƚŚĞŝŶĨůƵĞŶĐĞŽĨƉĂƚŝĞŶƚĐŽŶĚŝƚŝŽŶŽŶŬĂ͘Eͬ͗ŶŽƚ ĂƉƉůŝĐĂďůĞ͘  

(14)

M

ANUS

C

R

IP

T

ACCEP

TED

WĂŐĞϭϯŽĨϭϯ >ĞŐĞŶĚƚŽƚŚĞĨŝŐƵƌĞƐ͘ &ŝŐƵƌĞϭ͗ĐŽŶĐĞŶƚƌĂƚŝŽŶͲƚŝŵĞƉƌŽĨŝůĞƐŽĨƐŝƌŽůŝŵƵƐ;ͿĂŶĚƉŽƐĂĐŽŶĂnjŽůĞ;Ϳ͘ ^ŝƌŽůŝŵƵƐǁĂƐĂĚŵŝŶŝƐƚĞƌĞĚĂƐϱŵŐYĂŶĚƉŽƐĂĐŽŶĂnjŽůĞĂƐϯϬϬŵŐƚǁŝĐĞƚŚĞĨŝƌƐƚĚĂLJĂŶĚ ƚŚĞŶϯϬϬŵŐYĚƵƌŝŶŐϮϬĚĂLJƐ͕ĂŶĚƚŚĞŶϮϬϬŵŐY͘ĨƚĞƌƉŽƐĂĐŽŶĂnjŽůĞǁĂƐďĞŐƵŶ͕ƚǁŽ ƐƵďƐĞƋƵĞŶƚĚŽƐĞƐŽĨƐŝƌŽůŝŵƵƐǁĞƌĞŐŝǀĞŶ͕ďĞĨŽƌĞƚĞŵƉŽƌĂƌLJĚŝƐĐŽŶƚŝŶƵĂƚŝŽŶƵŶƚŝůƚŚĞϮϱƚŚ ĚĂLJ;ϲϬϬƚŚŚŽƵƌͿ͘^ŝƌŽůŝŵƵƐǁĂƐƚŚĞŶƌĞŝŶƚƌŽĚƵĐĞĚĂƚϱŵŐƚǁŝĐĞĂǁĞĞŬ͕ĂŶĚƚŚĞŶƐĞǀĞƌĂů ĚŽƐĞƌĞŐŝŵĞŶƐǁĞƌĞƚĞƐƚĞĚ͘&ŝŶĂůůLJ͕ϯŵŐƚǁŝĐĞĂǁĞĞŬǁĂƐĨŽƵŶĚƚŽďĞƐƚĨŝƚƚŽƚŚĞƉĂƚŝĞŶƚ͛Ɛ ŶĞĞĚƐ͘&ƵůůůŝŶĞŝƐƚŚĞƐŝŵƵůĂƚĞĚĐŽŶĐĞŶƚƌĂƚŝŽŶͲƚŝŵĞƉƌŽĨŝůĞ͕ƉŽŝŶƚƐĂƌĞƚŚĞŵĞĂƐƵƌĞĚƉůĂƐŵĂ ĐŽŶĐĞŶƚƌĂƚŝŽŶƐ͘ &ŝŐƵƌĞϮ͗ŽƐŝŶŐƐŝŵƵůĂƚŝŽŶƐ͘ ͘^ŝƌŽůŝŵƵƐϱŵŐY͘͘^ŝƌŽůŝŵƵƐϱŵŐYĂŶĚƚŚĞŶϮ͘ϱŵŐYĨƌŽŵƉŽƐĂĐŽŶĂnjŽůĞ ďĞŐŝŶŶŝŶŐ;ϱϬйĚŽƐĞƌĞĚƵĐƚŝŽŶͿ͘͘^ŝƌŽůŝŵƵƐϱŵŐYĂŶĚƚŚĞŶϭŵŐY;ϴϬйĚŽƐĞ ƌĞĚƵĐƚŝŽŶͿ͘͘^ŝƌŽůŝŵƵƐϱŵŐYĂŶĚƚŚĞŶϯŵŐ;ϰϬйĚŽƐĞƌĞĚƵĐƚŝŽŶͿĞǀĞƌLJƚŚƌĞĞĚĂLJƐ͘ WŽƐĂĐŽŶĂnjŽůĞǁĂƐďĞŐƵŶĂƚƚŚĞϰϴƚŚŚŽƵƌ͕ŐŝǀĞŶĂƐŽŶĞƚĂďůĞƚŽĨϯϬϬŵŐŽŶƚŚĞϰϴƚŚĂŶĚϲϬƚŚ ŚŽƵƌƐ͕ĂŶĚƚŚĞŶϯϬϬŵŐYĨƌŽŵƚŚĞϳϮƚŚŚŽƵƌ͘WŽƐĂĐŽŶĂnjŽůĞƉĂƌĂŵĞƚĞƌƐǁĞƌĞĨŝdžĞĚƐŽĂƐƚŽ ĂĐŚŝĞǀĞƐƚĞĂĚLJƐƚĂƚĞĂƚƚŚĞƚŚŝƌĚĚŽƐĞ;ϳϮƚŚŚŽƵƌͿǁŝƚŚƚƌŽƵŐŚĐŽŶĐĞŶƚƌĂƚŝŽŶƐŽĨϮђŐͬŵ>͘dŚĞ ĨƵůůůŝŶĞƌĞƉƌĞƐĞŶƚƐƚŚĞŵĞĂŶƐŝŵƵůĂƚĞĚƐŝƌŽůŝŵƵƐĐŽŶĐĞŶƚƌĂƚŝŽŶ͕ĚĂƌŬŐƌĞLJĂƌĞĂŝƐĨƌŽŵƚŚĞ ϮϱƚŚƚŽƚŚĞϳϱƚŚƉĞƌĐĞŶƚŝůĞ͕ĂŶĚůŝŐŚƚŐƌĞLJĂƌĞĂƐĂƌĞĨƌŽŵƚŚĞϱƚŚƚŽƚŚĞϮϱƚŚƉĞƌĐĞŶƚŝůĞĂŶĚ ĨƌŽŵƚŚĞϳϱƚŚƚŽƚŚĞϵϱƚŚƉĞƌĐĞŶƚŝůĞ͘

(15)

M

ANUS

C

R

IP

T

ACCEP

(16)

M

ANUS

C

R

IP

T

ACCEP

Références

Documents relatifs

This analysis included patients enrolled in the DESSOLVE I and II trials (DES with Sirolimus and a Bioabsorbable Polymer for the Treatment of Patients with De Novo Lesions in

L’omniprésence du « je » tout au long de la narration est une des techniques dont l’auteur a mis en œuvre pour établir une atmosphère imprégnée de réalité .Ce « je »

The methods can be applied to any other cases provided the required (or similar) data are available: (1) a sample of establishments at the building geographical level, (2)

Increasing pressure during sintering led to two noticeable effects: (i) a decrease of the permittivity (despite of the increase in ceramic density) and (ii) a variation of the

Using three representative examples of such systems from the fields of spreading processes, smart manufacturing, and transport phenomena, this thesis (i) developed

These are the aims of the present study. In the following, we first present the theoretical background re- quired to interpret active-DTS experiments before presenting the

En effet, dans ce lieu, vous trouverez tout ce qu’il vous faut pour être en forme toute l’année: des produits naturels et bio tels que des compléments alimen- taires, des cristaux

The superposition of the crystal structures of the two ligand- free forms of EryK (Fig. 2C), obtained at low and high salt, reveals that there are two different conformations for