49d024497019561889e797b6a4df56ed pmc_32244303.pdf 4a98abee33570fc2aa0879a8f0ed8fe600a92b0b pmc_32244303.pdf db327280a70a21afa5cbb3f4c2d9e68bdcc37ab044959ddc8d9f3bf59dfdba31 pmc_32244303.pdf Title: Characterization of a CholesteroNitrone (ISQ-201), a Novel Drug Candidate for the Treatment of Ischemic Stroke Subject: Nitrones have a well-recognized capacity as spin-traps and are considered powerful free radical scavengers, which are two important issues in hypoxia-induced oxidative stress and cell death in brain ischemia. Consequently, nitrones have been proposed as therapeutic agents in acute ischemic stroke (AIS). In this paper, we update the biological and pharmacological characterization of ISQ-201, a previously identified cholesteronitrone hybrid with antioxidant and neuroprotective activity. This study characterizes ISQ-201 as a neuroprotective agent against the hypoxia-induced ischemic injury. Transitory four-vessel occlusion and middle cerebral artery occlusion (tMCAO) were used to induce cerebral ischemia. Functional outcomes were determined using neurofunctional tests. Infarct area, neuronal death, and apoptosis induction were evaluated. In addition, ISQ-201 reactivity towards free radicals was studied in a theoretical model. ISQ-201 significantly decreased the ischemia-induced neuronal death and apoptosis, in a dose-dependent manner, showing its therapeutic effect when administered up until 6 h after post-ischemic reperfusion onset, effects that remained after 3 months from the ischemic episode. Furthermore, ISQ-201 significantly reduced infarct volume, leading to recovery of the motor function in the tMCAO model. Finally, the theoretical study confirmed the reactivity of ISQ-201 towards hydroxyl radicals. The results reported here prompted us to suggest ISQ-201 as a promising candidate for the treatment of AIS. Keywords: antioxidant; brain ischemia; hydroxyl radical; ischemic stroke; neuroprotection; nitrones; steroids; reactive oxygen species Author: Emma Martínez-Alonso, Alejandro Escobar-Peso, Maria I. Ayuso, Rafael Gonzalo-Gobernado, Mourad Chioua, Juan J. 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Title: ぉのぴひはつふっぴどはのぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸲ Item: Title: きちぴづひどちぬびぜ〴ぜ〰ちのつぜ〴ぜ〰きづぴとはつびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮ㄩ‾㸊⡜㌷㙜㌷㝜〰ぃはねばふぴちぴどはのちぬぜ〴ぜ〰きづぴとはつびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㈩‾㸊⡜㌷㙜㌷㝜〰こべのぴとづびどびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㌩‾㸊⡜㌷㙜㌷㝜〰ぐとちひねちっはにどのづぴどっびぜ〴ぜ〰こぴふつべぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㐩‾㸊⡜㌷㙜㌷㝜〰ぁのどねちぬぜ〴ぜ〰きはつづぬぜ〴ぜ〰はてぜ〴ぜ〰ぇぬはぢちぬぜ〴ぜ〰ぃづひづぢひちぬぜ〴ぜ〰ぉびっとづねどち〬ぜ〴ぜ〰ぅへばづひどねづのぴちぬぜ〴ぜ〰いづびどでの〬ぜ〴ぜ〰ちのつぜ〴ぜ〰ごひづちぴねづのぴぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㔩‾㸊⡜㌷㙜㌷㝜〰ぅぶちぬふちぴどはのぜ〴ぜ〰はてぜ〴ぜ〰ぎづふひはぬはでどっちぬぜ〴ぜ〰いづてどっどぴびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㘩‾㸊⡜㌷㙜㌷㝜〰あづとちぶどはひちぬぜ〴ぜ〰ごづびぴびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㜩‾㸊⡜㌷㙜㌷㝜〰あひちどのぜ〴ぜ〰こづっぴどはのびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㠩‾㸊⡜㌷㙜㌷㝜〰ぎづふひはのちぬぜ〴ぜ〰いづちぴとぜ〴ぜ〰ぅぶちぬふちぴどはのぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㤩‾㸊⡜㌷㙜㌷㝜〰ごさぎぅがぜ〴ぜ〰ぁびびちべぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㄰ Children: Item: Title: ぃはねばふぴちぴどはのちぬぜ〴ぜ〰きづぴとはつびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㈩‾㸊⡜㌷㙜㌷㝜〰こべのぴとづびどびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㌩‾㸊⡜㌷㙜㌷㝜〰ぐとちひねちっはにどのづぴどっびぜ〴ぜ〰こぴふつべぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㐩‾㸊⡜㌷㙜㌷㝜〰ぁのどねちぬぜ〴ぜ〰きはつづぬぜ〴ぜ〰はてぜ〴ぜ〰ぇぬはぢちぬぜ〴ぜ〰ぃづひづぢひちぬぜ〴ぜ〰ぉびっとづねどち〬ぜ〴ぜ〰ぅへばづひどねづのぴちぬぜ〴ぜ〰いづびどでの〬ぜ〴ぜ〰ちのつぜ〴ぜ〰ごひづちぴねづのぴぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㔩‾㸊⡜㌷㙜㌷㝜〰ぅぶちぬふちぴどはのぜ〴ぜ〰はてぜ〴ぜ〰ぎづふひはぬはでどっちぬぜ〴ぜ〰いづてどっどぴびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㘩‾㸊⡜㌷㙜㌷㝜〰あづとちぶどはひちぬぜ〴ぜ〰ごづびぴびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㜩‾㸊⡜㌷㙜㌷㝜〰あひちどのぜ〴ぜ〰こづっぴどはのびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㠩‾㸊⡜㌷㙜㌷㝜〰ぎづふひはのちぬぜ〴ぜ〰いづちぴとぜ〴ぜ〰ぅぶちぬふちぴどはのぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㤩‾㸊⡜㌷㙜㌷㝜〰ごさぎぅがぜ〴ぜ〰ぁびびちべぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㄰ Item: Title: こべのぴとづびどびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㌩‾㸊⡜㌷㙜㌷㝜〰ぐとちひねちっはにどのづぴどっびぜ〴ぜ〰こぴふつべぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㐩‾㸊⡜㌷㙜㌷㝜〰ぁのどねちぬぜ〴ぜ〰きはつづぬぜ〴ぜ〰はてぜ〴ぜ〰ぇぬはぢちぬぜ〴ぜ〰ぃづひづぢひちぬぜ〴ぜ〰ぉびっとづねどち〬ぜ〴ぜ〰ぅへばづひどねづのぴちぬぜ〴ぜ〰いづびどでの〬ぜ〴ぜ〰ちのつぜ〴ぜ〰ごひづちぴねづのぴぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㔩‾㸊⡜㌷㙜㌷㝜〰ぅぶちぬふちぴどはのぜ〴ぜ〰はてぜ〴ぜ〰ぎづふひはぬはでどっちぬぜ〴ぜ〰いづてどっどぴびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㘩‾㸊⡜㌷㙜㌷㝜〰あづとちぶどはひちぬぜ〴ぜ〰ごづびぴびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㜩‾㸊⡜㌷㙜㌷㝜〰あひちどのぜ〴ぜ〰こづっぴどはのびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㠩‾㸊⡜㌷㙜㌷㝜〰ぎづふひはのちぬぜ〴ぜ〰いづちぴとぜ〴ぜ〰ぅぶちぬふちぴどはのぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㤩‾㸊⡜㌷㙜㌷㝜〰ごさぎぅがぜ〴ぜ〰ぁびびちべぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㄰ Item: Title: ぐとちひねちっはにどのづぴどっびぜ〴ぜ〰こぴふつべぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㐩‾㸊⡜㌷㙜㌷㝜〰ぁのどねちぬぜ〴ぜ〰きはつづぬぜ〴ぜ〰はてぜ〴ぜ〰ぇぬはぢちぬぜ〴ぜ〰ぃづひづぢひちぬぜ〴ぜ〰ぉびっとづねどち〬ぜ〴ぜ〰ぅへばづひどねづのぴちぬぜ〴ぜ〰いづびどでの〬ぜ〴ぜ〰ちのつぜ〴ぜ〰ごひづちぴねづのぴぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㔩‾㸊⡜㌷㙜㌷㝜〰ぅぶちぬふちぴどはのぜ〴ぜ〰はてぜ〴ぜ〰ぎづふひはぬはでどっちぬぜ〴ぜ〰いづてどっどぴびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㘩‾㸊⡜㌷㙜㌷㝜〰あづとちぶどはひちぬぜ〴ぜ〰ごづびぴびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㜩‾㸊⡜㌷㙜㌷㝜〰あひちどのぜ〴ぜ〰こづっぴどはのびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㠩‾㸊⡜㌷㙜㌷㝜〰ぎづふひはのちぬぜ〴ぜ〰いづちぴとぜ〴ぜ〰ぅぶちぬふちぴどはのぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㤩‾㸊⡜㌷㙜㌷㝜〰ごさぎぅがぜ〴ぜ〰ぁびびちべぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㄰ Item: Title: ぁのどねちぬぜ〴ぜ〰きはつづぬぜ〴ぜ〰はてぜ〴ぜ〰ぇぬはぢちぬぜ〴ぜ〰ぃづひづぢひちぬぜ〴ぜ〰ぉびっとづねどち〬ぜ〴ぜ〰ぅへばづひどねづのぴちぬぜ〴ぜ〰いづびどでの〬ぜ〴ぜ〰ちのつぜ〴ぜ〰ごひづちぴねづのぴぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㔩‾㸊⡜㌷㙜㌷㝜〰ぅぶちぬふちぴどはのぜ〴ぜ〰はてぜ〴ぜ〰ぎづふひはぬはでどっちぬぜ〴ぜ〰いづてどっどぴびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㘩‾㸊⡜㌷㙜㌷㝜〰あづとちぶどはひちぬぜ〴ぜ〰ごづびぴびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㜩‾㸊⡜㌷㙜㌷㝜〰あひちどのぜ〴ぜ〰こづっぴどはのびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㠩‾㸊⡜㌷㙜㌷㝜〰ぎづふひはのちぬぜ〴ぜ〰いづちぴとぜ〴ぜ〰ぅぶちぬふちぴどはのぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㤩‾㸊⡜㌷㙜㌷㝜〰ごさぎぅがぜ〴ぜ〰ぁびびちべぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㄰ Item: Title: ぅぶちぬふちぴどはのぜ〴ぜ〰はてぜ〴ぜ〰ぎづふひはぬはでどっちぬぜ〴ぜ〰いづてどっどぴびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㘩‾㸊⡜㌷㙜㌷㝜〰あづとちぶどはひちぬぜ〴ぜ〰ごづびぴびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㜩‾㸊⡜㌷㙜㌷㝜〰あひちどのぜ〴ぜ〰こづっぴどはのびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㠩‾㸊⡜㌷㙜㌷㝜〰ぎづふひはのちぬぜ〴ぜ〰いづちぴとぜ〴ぜ〰ぅぶちぬふちぴどはのぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㤩‾㸊⡜㌷㙜㌷㝜〰ごさぎぅがぜ〴ぜ〰ぁびびちべぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㄰ Item: Title: あづとちぶどはひちぬぜ〴ぜ〰ごづびぴびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㜩‾㸊⡜㌷㙜㌷㝜〰あひちどのぜ〴ぜ〰こづっぴどはのびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㠩‾㸊⡜㌷㙜㌷㝜〰ぎづふひはのちぬぜ〴ぜ〰いづちぴとぜ〴ぜ〰ぅぶちぬふちぴどはのぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㤩‾㸊⡜㌷㙜㌷㝜〰ごさぎぅがぜ〴ぜ〰ぁびびちべぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㄰ Item: Title: あひちどのぜ〴ぜ〰こづっぴどはのびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㠩‾㸊⡜㌷㙜㌷㝜〰ぎづふひはのちぬぜ〴ぜ〰いづちぴとぜ〴ぜ〰ぅぶちぬふちぴどはのぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㤩‾㸊⡜㌷㙜㌷㝜〰ごさぎぅがぜ〴ぜ〰ぁびびちべぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㄰ Item: Title: ぎづふひはのちぬぜ〴ぜ〰いづちぴとぜ〴ぜ〰ぅぶちぬふちぴどはのぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㤩‾㸊⡜㌷㙜㌷㝜〰ごさぎぅがぜ〴ぜ〰ぁびびちべぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㄰ Item: Title: ごさぎぅがぜ〴ぜ〰ぁびびちべぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㄰ Item: Title: ぁのどねちぬぜ〴ぜ〰きはつづぬぜ〴ぜ〰はてぜ〴ぜ〰うはっちぬぜ〴ぜ〰ぃづひづぢひちぬぜ〴ぜ〰ぉびっとづねどちぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮ㄱ Item: Title: きはぴはひ〭いづてどっどぴぜ〴ぜ〰ぅぶちぬふちぴどはの〬ぜ〴ぜ〰ぇひどばぜ〴ぜ〰こぴひづのでぴとぜ〴ぜ〰ごづびぴぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮ㄲ Item: Title: ぉのてちひっぴぜ〴ぜ〰ざはぬふねづぜ〴ぜ〰ぅぶちぬふちぴどはのぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮ㄳ Item: Title: こぴちぴどびぴどっちぬぜ〴ぜ〰ぁのちぬべびどびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸳ Item: Title: げづびふぬぴびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㌮ㄩ‾㸊⡜㌷㙜㌷㝜〰ぉのぜ〴ぜ〰こどぬどっはぜ〴ぜ〰いうご〭こぴふつべぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㌮㈩‾㸊⡜㌷㙜㌷㝜〰いはびづ〭げづびばはのびづぜ〴ぜ〰こぴふつべぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獵扳散瑩潮⸳⸲⸱ Children: Item: Title: ぉのぜ〴ぜ〰こどぬどっはぜ〴ぜ〰いうご〭こぴふつべぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㌮㈩‾㸊⡜㌷㙜㌷㝜〰いはびづ〭げづびばはのびづぜ〴ぜ〰こぴふつべぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獵扳散瑩潮⸳⸲⸱ Item: Title: いはびづ〭げづびばはのびづぜ〴ぜ〰こぴふつべぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獵扳散瑩潮⸳⸲⸱ Children: Item: Title: ぁのちぬべびどびぜ〴ぜ〰はてぜ〴ぜ〰ぎづふひはのちぬぜ〴ぜ〰いづちぴとぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獵扳散瑩潮⸳⸲⸲ Item: Title: ぁのちぬべびどびぜ〴ぜ〰はてぜ〴ぜ〰ぎづふひはのちぬぜ〴ぜ〰ぁばはばぴはびどびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獵扳散瑩潮⸳⸲⸳ Item: Title: いはびづ〭げづびばはのびづぜ〴ぜ〰ぃふひぶづぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㌮㌩‾㸊⡜㌷㙜㌷㝜〰ごとづひちばづふぴどっぜ〴ぜ〰しどのつはぷぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獵扳散瑩潮⸳⸳⸱ Item: Title: ごとづひちばづふぴどっぜ〴ぜ〰しどのつはぷぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獵扳散瑩潮⸳⸳⸱ Children: Item: Title: ぁのちぬべびどびぜ〴ぜ〰はてぜ〴ぜ〰ぎづふひはのちぬぜ〴ぜ〰いづちぴとぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獵扳散瑩潮⸳⸳⸲ Item: Title: ぁのちぬべびどびぜ〴ぜ〰はてぜ〴ぜ〰ぎづふひはのちぬぜ〴ぜ〰ぁばはばぴはびどびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獵扳散瑩潮⸳⸳⸳ Item: Title: うふのっぴどはのちぬぜ〴ぜ〰ごづびぴぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㌮㐩‾㸊⡜㌷㙜㌷㝜〰がはので〭ごづひねぜ〴ぜ〰ぅててどっちっべぜ〴ぜ〰ぁびびづびびねづのぴぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獵扳散瑩潮⸳⸴⸱ Item: Title: がはので〭ごづひねぜ〴ぜ〰ぅててどっちっべぜ〴ぜ〰ぁびびづびびねづのぴぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獵扳散瑩潮⸳⸴⸱ Children: Item: Title: ぁのちぬべびどびぜ〴ぜ〰はてぜ〴ぜ〰ぎづふひはのちぬぜ〴ぜ〰ざどちぢどぬどぴべぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獵扳散瑩潮⸳⸴⸲ Item: Title: あづとちぶどはひちぬぜ〴ぜ〰ごづびぴびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㌮㔩‾㸊⡜㌷㙜㌷㝜〰ぐとちひねちっはにどのづぴどっぜ〴ぜ〰こぴふつべぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㌮㘩‾㸊⡜㌷㙜㌷㝜〰ぉこけ〭〲〰〱ぜ〴ぜ〰ごひづちぴねづのぴぜ〴ぜ〰どのぜ〴ぜ〰ごひちのびどづのぴぜ〴ぜ〰うはっちぬぜ〴ぜ〰ぃづひづぢひちぬぜ〴ぜ〰ぉびっとづねどちぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸴ Item: Title: ぐとちひねちっはにどのづぴどっぜ〴ぜ〰こぴふつべぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㌮㘩‾㸊⡜㌷㙜㌷㝜〰ぉこけ〭〲〰〱ぜ〴ぜ〰ごひづちぴねづのぴぜ〴ぜ〰どのぜ〴ぜ〰ごひちのびどづのぴぜ〴ぜ〰うはっちぬぜ〴ぜ〰ぃづひづぢひちぬぜ〴ぜ〰ぉびっとづねどちぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸴ Item: Title: ぉこけ〭〲〰〱ぜ〴ぜ〰ごひづちぴねづのぴぜ〴ぜ〰どのぜ〴ぜ〰ごひちのびどづのぴぜ〴ぜ〰うはっちぬぜ〴ぜ〰ぃづひづぢひちぬぜ〴ぜ〰ぉびっとづねどちぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸴ Item: Title: いどびっふびびどはのぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸵ Item: Title: ぃはのっぬふびどはのびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸶ Item: Title: ぐちぴづのぴびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸶ Item: Title: げづてづひづのっづび Filters: FilterPipeline: FlateDecode Fonts: Type1: Font: BaseFont: CKITET+URWPalladioL-Bold FontSubset: true FirstChar: 3 LastChar: 150 FontDescriptor: FontName: CKITET+URWPalladioL-Bold Flags: Symbolic FontBBox: -152, -301, 1000, 935 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: IOJCNK+VnURWPalladioL-Bold FontSubset: true FirstChar: 161 LastChar: 189 FontDescriptor: FontName: IOJCNK+VnURWPalladioL-Bold Flags: Symbolic FontBBox: -152, -301, 1000, 935 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: UFDEMN+URWPalladioL-Roma FontSubset: true FirstChar: 2 LastChar: 241 FontDescriptor: FontName: UFDEMN+URWPalladioL-Roma Flags: Symbolic FontBBox: -166, -283, 1021, 943 FontFile: true EncodingDictionary: Differences: true 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