葱白提取物防治兔创伤性下肢深静脉血栓形成的机制研究
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摘要
目的
构建兔下肢创伤性下肢深静脉血栓(deep vein thrombosis, DVT)模型,也就是中医学“股肿”的模型。应用现代先进医学仪器观察通阳中药葱白提取物对兔创伤性下肢DVT模型凝血、抗凝功能、纤溶功能、炎性因子、抗氧化损伤等诸多现代医学指标的变化,进而探讨葱白提取物防治兔创伤性DVT的机制,旨在为葱白提取物在防治DVT方面提供直接而客观的现代医学证据。
方法
1.随机将新西兰白兔24只分为模型对照组、葱白治疗组和葱白防治组。按照赵学凌的方法构建兔下肢创伤性DVT模型,造模成功后,模型对照组给予生理盐水1周,葱白治疗组给予葱白提取物1周,葱白防治组造模前持续给予葱白提取物1周,造模后同葱白治疗组。
2.检测以下指标：(1)造模前后P-选择素(CD62P)、血小板活化因子(PAF)和溶酶体膜蛋白(CD63)的变化；(2)造模前后血小板膜糖蛋白(GPⅡb/Ⅲa)及凝血酶受体-1 (PAR-1)、凝血酶受体-4(PAR-4)的变化；(3)造模前后各组活化蛋白C (APC)和血浆前体蛋白(TpP)的变化；(4)造模前后各组凝血功能、血浆凝血酶调节蛋白(TM)和D-二聚体(D-D)的变化；(5)造模前后组织型纤溶酶原活化剂(t-PA)、纤溶酶原活化剂抑制物(PAI)的变化；(6)造模前后各组血液流变学的变化；(7)造模前后血清白细胞介素6(IL-6)、白细胞介素8(IL-8)的变化；(8)造模前后各组超氧化物岐化酶(SOD)和丙二醛(MDA)的变化。
结果
大体观察模型对照组、葱白治疗组和葱白防治组造模成功后,双下肢均出现不同程度的弥散性肿胀,但防治组造模后其肿胀程度明显低于模型对照组及治疗组。造模7天后拆除石膏三组兔子均无明显的肿胀,但皮下淤血面积葱白防治组较模型对照组及葱白治疗组小,其中葱白治疗组1只和模型对照组2只兔子在拆除石膏时突然死亡,经解剖确认为肺栓塞死亡。按照赵学凌等造模方法,报道形成兔下肢创伤性DVT模型约占80%,我们前期预实验结果与此接近,如果没有血栓,也有检测数值上的变化。
1.造模后,各组兔血清中CD62P、PAF、CD63含量明显升高,葱白防治组和葱白治疗组均可以降低模型对照组兔血清中CD62P、PAF、CD63含量,葱白防治组优于葱白治疗组。
2.造模后,各组兔血清中GPⅡb/Ⅲa及PAR-1、PAR-4含量明显升高,葱白防治组和葱白治疗组均可以降低模型对照组兔血清中GPⅡb/Ⅲa及PAR-1、PAR-4表达,葱白防治组优于葱白治疗组。
3.造模后各组兔子血浆中APC明显降低,TpP明显升高,葱白防治组和葱白治疗组可升高APC,降低TpP,有统计学意义；葱白防治组各时段均优于葱白治疗组。
4.造模前各组凝血功能、TM和D-D水平无显著差异,造模后各时段葱白防治组对各项指标的影响均优于葱白治疗组。
5.造模后,各组兔血清中t-PA含量明显降低,PAI含量明显升高；葱白治疗组第7天可以明显升高t-PA水平,葱白防治组各时段t-PA水平均没有改变,葱白治疗组疗效优于葱白防治组；葱白防治组各时段PAI的水平明显降低,疗效优于葱白治疗组。
6.造模后,葱白防治组的全血粘度(ηb)、血浆粘度(ηp)、红细胞聚集指数(EAI)与模型对照组、葱白治疗组比较有显著差异,葱白治疗组与模型对照组相比较差异第七天有统计学意义；葱白防治组各时段均优于葱白治疗组,EAI各时段组间变化无统计学意义。
7.造模后,各组兔血清中IL-6、IL-8含量明显升高,葱白预防组和葱白治疗组均可以降低兔血清中IL-6、IL-8含量,各时段组间没有统计学意义。
8.与治疗前比较,各组血清SOD水平明显下降,MDA水平明显增加；与模型对照组比较,葱白防治组和葱白治疗组各时段均有统计学意义；葱白防治组各时段均优于葱白治疗组。
结论
1.通阳中药葱白提取物可以有效的防治创伤性DVT,机制是：(1)阻碍血小板活化,·减少组织因子表达,抑制血小板聚集；(2)灭活凝血因子,降低凝血酶的活性,改善高凝状态；(3)改善纤溶功能,影响纤维蛋白的形成与降解,保持正常的纤溶活性；(4)改善血流状态,加速侧支循环建立,促进血液循环；(5)减少炎症因子的表达,升高凝血抑制因子,防止高凝状态；(6)清除氧自由基,保护血管内皮,抗氧化损伤。
2.本研究结果证实：(1)“股肿”的主要病机是“痰瘀痹阻”,阳气之失于条达畅通是“痰瘀痹阻”的关键环节,也是治疗本病的枢机所在。(2)关于痰瘀同病的治法：通阳法不失为除化痰、活血之外治疗股肿的又一治法。(3)辛温可通阳,阳气畅达,则痰可化瘀可祛,经脉通达,脉痹可除。通过恢复或激活阳气的条达,减轻病理损伤,延缓病理进程,阻断病情的循环加重,使病理变化向良性循环恢复,进而使各脏腑经络的功能得以正常发挥。因而葱白提取物可以用于防治股肿即DVT。
Objective
We built the models of rabbits'lower limbs traumatic deep vein thrombosi s, which is called "Thigh-Swollen" in TCM. We applied modern advanced me dical instruments to test the changes of many modern medical indicators in the models of rabbits'Traumatic lower limbs of deep vein thrombosis(DVT), whi ch were caused by Onion stalk extraction(OSE) with the "activating yang " fu nction in traditional Chinese medicine,such as:Blood coagulation function, a int-Blood coagulation function, fibrinolytic function, inflammatory factor, ant ioxidant injury,and then to discuss the mechanism of the Onion stalk extracti on on prevention and treatment of rabbits' Traumatic lower limbs of DVT, we are aimed at providing direct and objective modern medical evidence of OSE on prevention and Treatment of Rabbits'Traumatic DVT.
Methods
1.24 New Zealand white rabbits were randomly divided into three groups:co ntrol group, OSE prevention group and OSE treatment group. according to Zh ao Xueling's method, we built the animal models of Traumatic lower limbs of deep vein thrombosis DVT,then, give Saline solution and Onion stalk extract ion respectively to control group and OSE treatment group for 1 week, but for prevention group, we give Onion stalk extraction consecutively for 1 week bef ore models had been built. After the models were built, the same with OSE tre atment group.
2. Testing the following indicators of each group before and after the models were built:(1)the level of P-selectin (CD62P), platelet activating factor (PAF), lysosomal membrane protein (CD63); (2)the level of Glycoprotain II b/IIIa (G PⅡb/Ⅲa),protease activated receptor-1 (PAR-1),protease activated receptor-4 (PAR-4); (3)the level of activated protein C(APC) and thrombus precursor pr otein (TpP);(4)the level of blood clotting, plasma thrombomodulin (TM) and D-dimer(D-D);(5)the level of tissue-type plasminogen activator(t-PA) and pl asminogen activator inhibitor(PAI);(6) the changes of hemorheolgy before an d after the modeling;(7)the level of Interleukelin-6(IL-6) and Interleukelin-8 (IL-8);(8)the level of Superoxide dismutase(SOD) and Malondialdehyde (M DA).
Results
General observation:Diffuse both lower limbs swelling of rabbits can be observed in all the three groups after modeling, while in OSE prevention gro up, swelling was significantly lesser than control group and OSE treatment gr oup. No significant swelling can be observed in the three groups when remo ving plaster on the 7th day later after modeling; however, the subcutaneous congestion areas were smaller in OSE prevention group than control group and OSE treatment group, while, one rabbit in the OSE treatment group and two rabbits in the model group died suddenly when we removed the plaster, it was confirmed that the reason of the death is Pulmonary embolism (PE). According to Zhao Xueling's method, it was reported that the percent of the successful models is 80%, and the data is similar with our pre-experimental result, even though no thrombosis formed, there is changes in the indicators of testing.
1. After the models were built, the level of CD62P、PAF and CD63 in the ser um of each group increased significantly, however, the level of CD62P、PDF and CD63 decreased in both OSE prevention group and OSE treatment group, compared with the control group. The prevention group was superior to the tre atment group
2. The level of serum GPⅡb/Ⅲa and PAR-1、PAR-4 increased in every group. The expression level of serum GP II b/IIIa and PAR-1、PAR-4 were signific antly decreased in OSE prevention group and OSE treatment group. Compared with treatment group, the prevention group was superior to the treatment group
3. After the models were built, the APC of the plasma in each rabbit reduced significantly, and the TpP increased significantly. Both the OSE prevention group and the OSE treatment group can increase the level of APC, and reduce the level of TpP. The result was statistically significant. And the prevention group was superior to the treatment group in each period.
4. Before building the models, in each group, there are no significant differen ces in the indicators of blood clotting, TM and D-D levels. And after the mod els were built, the influences to each evaluation indicators of the OSE prevent ion group were superior to the treatment group.
5. After the models were built, the serum level of t-PA were significantly decre ased, and the level of PAI increased significantly. Then in the seventh day, the level of serum t-PA were increased in OSE treatment group, while no signific ant changes of serum t-PA were detected in OSE prevention group, OSE treat ment group is better than OSE prevention group. The level of PAI in all phase in OSE prevention group were decreased significantly, the curative effect of w hich is better than OSE treatment group.
6. after the models were built, there is significant difference in the level of wh ole blood viscosity (ηb)、plasma viscosity (ηp)、RBC aggregation index (EAI) in the OSE prevention group, compared with the control group and the treatment group, while, there is significant difference in the treatment gro up on the seventh day, compared with the control group. The OSE prevention group were superior to the treatment group in each phase, there is no statistical significance in the change of EAI in each phase.
7. After the models were built, the IL-6,IL-8 level of each rabbits'serum incre ased significantly, while, both the OSE prevention group and the treatment gro up can reduce the IL-6,IL-8 level of rabbits'serum in the models. And there is no statistical significant difference in the result of each phase.
8. Before the experimental treatment, the SOD level of each serum dropped si gnificantly, the MDA level increased obviously. Compared with the control gr oup, there is statistical significance in the result of the OSE prevention group a nd the treatment group, and the prevention group was superior to the treatment group in each period
Conclusion:
The mechanisms of OSE which can prevent and treat traumatic DVT effectivly are following:(1).Hindering the activation of the platelet, reducing the expression of tissue factor, inhibiting platelet aggregation; (2).Inactivating coagulation factors, reducing the activity of the thrombin, ameliorating the hyper-coagulation state;(3).ameliorating fibrin lytic function, influencing the formation and degradation of fibrin, maintaining the normal fibrin lytic activity;(4).Ameliorating the state of blood flow, accelerating establishing collateral circulation, promoting the blood circulation; (5). Reducing the expression of the inflammation factors, increasing the coagulation inhibitory factors, preventing hyper-coagulation state;(6). scavenging oxygen free radicals, protecting endotheliocyte, and antioxidant.
This study shows that:(1)The main pathogenesis of "Thigh-Swollen" is blockage of phlegm and blood stasis -Yang qi failing to act freely is the key point, (2) About the treatment method of coexistence of phlegm and blood stasis, the method of activating yang is a vital treatment for "Thigh- Swollen",besides the method of reducing phlegm and removing blood stasis.(3) Through recovering and activating of the Yang-qi, which can reduce the damage of the pathological process, delay the cycle of illness aggravating, and make the pathological changes to the benign circulatio,and then, the function of each of the Zang-fu organs and meridians can be exertion normally. Yang-qi is "pungent warm", which can remove the phlegm and make the meridians act freely. Thus, Onion stalk extraction can be used for prevention and treatment on "Thigh- Swollen" which is also called DVT.
构建兔下肢创伤性下肢深静脉血栓(deep vein thrombosis, DVT)模型,也就是中医学“股肿”的模型。应用现代先进医学仪器观察通阳中药葱白提取物对兔创伤性下肢DVT模型凝血、抗凝功能、纤溶功能、炎性因子、抗氧化损伤等诸多现代医学指标的变化,进而探讨葱白提取物防治兔创伤性DVT的机制,旨在为葱白提取物在防治DVT方面提供直接而客观的现代医学证据。
方法
1.随机将新西兰白兔24只分为模型对照组、葱白治疗组和葱白防治组。按照赵学凌的方法构建兔下肢创伤性DVT模型,造模成功后,模型对照组给予生理盐水1周,葱白治疗组给予葱白提取物1周,葱白防治组造模前持续给予葱白提取物1周,造模后同葱白治疗组。
2.检测以下指标：(1)造模前后P-选择素(CD62P)、血小板活化因子(PAF)和溶酶体膜蛋白(CD63)的变化；(2)造模前后血小板膜糖蛋白(GPⅡb/Ⅲa)及凝血酶受体-1 (PAR-1)、凝血酶受体-4(PAR-4)的变化；(3)造模前后各组活化蛋白C (APC)和血浆前体蛋白(TpP)的变化；(4)造模前后各组凝血功能、血浆凝血酶调节蛋白(TM)和D-二聚体(D-D)的变化；(5)造模前后组织型纤溶酶原活化剂(t-PA)、纤溶酶原活化剂抑制物(PAI)的变化；(6)造模前后各组血液流变学的变化；(7)造模前后血清白细胞介素6(IL-6)、白细胞介素8(IL-8)的变化；(8)造模前后各组超氧化物岐化酶(SOD)和丙二醛(MDA)的变化。
结果
大体观察模型对照组、葱白治疗组和葱白防治组造模成功后,双下肢均出现不同程度的弥散性肿胀,但防治组造模后其肿胀程度明显低于模型对照组及治疗组。造模7天后拆除石膏三组兔子均无明显的肿胀,但皮下淤血面积葱白防治组较模型对照组及葱白治疗组小,其中葱白治疗组1只和模型对照组2只兔子在拆除石膏时突然死亡,经解剖确认为肺栓塞死亡。按照赵学凌等造模方法,报道形成兔下肢创伤性DVT模型约占80%,我们前期预实验结果与此接近,如果没有血栓,也有检测数值上的变化。
1.造模后,各组兔血清中CD62P、PAF、CD63含量明显升高,葱白防治组和葱白治疗组均可以降低模型对照组兔血清中CD62P、PAF、CD63含量,葱白防治组优于葱白治疗组。
2.造模后,各组兔血清中GPⅡb/Ⅲa及PAR-1、PAR-4含量明显升高,葱白防治组和葱白治疗组均可以降低模型对照组兔血清中GPⅡb/Ⅲa及PAR-1、PAR-4表达,葱白防治组优于葱白治疗组。
3.造模后各组兔子血浆中APC明显降低,TpP明显升高,葱白防治组和葱白治疗组可升高APC,降低TpP,有统计学意义；葱白防治组各时段均优于葱白治疗组。
4.造模前各组凝血功能、TM和D-D水平无显著差异,造模后各时段葱白防治组对各项指标的影响均优于葱白治疗组。
5.造模后,各组兔血清中t-PA含量明显降低,PAI含量明显升高；葱白治疗组第7天可以明显升高t-PA水平,葱白防治组各时段t-PA水平均没有改变,葱白治疗组疗效优于葱白防治组；葱白防治组各时段PAI的水平明显降低,疗效优于葱白治疗组。
6.造模后,葱白防治组的全血粘度(ηb)、血浆粘度(ηp)、红细胞聚集指数(EAI)与模型对照组、葱白治疗组比较有显著差异,葱白治疗组与模型对照组相比较差异第七天有统计学意义；葱白防治组各时段均优于葱白治疗组,EAI各时段组间变化无统计学意义。
7.造模后,各组兔血清中IL-6、IL-8含量明显升高,葱白预防组和葱白治疗组均可以降低兔血清中IL-6、IL-8含量,各时段组间没有统计学意义。
8.与治疗前比较,各组血清SOD水平明显下降,MDA水平明显增加；与模型对照组比较,葱白防治组和葱白治疗组各时段均有统计学意义；葱白防治组各时段均优于葱白治疗组。
结论
1.通阳中药葱白提取物可以有效的防治创伤性DVT,机制是：(1)阻碍血小板活化,·减少组织因子表达,抑制血小板聚集；(2)灭活凝血因子,降低凝血酶的活性,改善高凝状态；(3)改善纤溶功能,影响纤维蛋白的形成与降解,保持正常的纤溶活性；(4)改善血流状态,加速侧支循环建立,促进血液循环；(5)减少炎症因子的表达,升高凝血抑制因子,防止高凝状态；(6)清除氧自由基,保护血管内皮,抗氧化损伤。
2.本研究结果证实：(1)“股肿”的主要病机是“痰瘀痹阻”,阳气之失于条达畅通是“痰瘀痹阻”的关键环节,也是治疗本病的枢机所在。(2)关于痰瘀同病的治法：通阳法不失为除化痰、活血之外治疗股肿的又一治法。(3)辛温可通阳,阳气畅达,则痰可化瘀可祛,经脉通达,脉痹可除。通过恢复或激活阳气的条达,减轻病理损伤,延缓病理进程,阻断病情的循环加重,使病理变化向良性循环恢复,进而使各脏腑经络的功能得以正常发挥。因而葱白提取物可以用于防治股肿即DVT。
Objective
We built the models of rabbits'lower limbs traumatic deep vein thrombosi s, which is called "Thigh-Swollen" in TCM. We applied modern advanced me dical instruments to test the changes of many modern medical indicators in the models of rabbits'Traumatic lower limbs of deep vein thrombosis(DVT), whi ch were caused by Onion stalk extraction(OSE) with the "activating yang " fu nction in traditional Chinese medicine,such as:Blood coagulation function, a int-Blood coagulation function, fibrinolytic function, inflammatory factor, ant ioxidant injury,and then to discuss the mechanism of the Onion stalk extracti on on prevention and treatment of rabbits' Traumatic lower limbs of DVT, we are aimed at providing direct and objective modern medical evidence of OSE on prevention and Treatment of Rabbits'Traumatic DVT.
Methods
1.24 New Zealand white rabbits were randomly divided into three groups:co ntrol group, OSE prevention group and OSE treatment group. according to Zh ao Xueling's method, we built the animal models of Traumatic lower limbs of deep vein thrombosis DVT,then, give Saline solution and Onion stalk extract ion respectively to control group and OSE treatment group for 1 week, but for prevention group, we give Onion stalk extraction consecutively for 1 week bef ore models had been built. After the models were built, the same with OSE tre atment group.
2. Testing the following indicators of each group before and after the models were built:(1)the level of P-selectin (CD62P), platelet activating factor (PAF), lysosomal membrane protein (CD63); (2)the level of Glycoprotain II b/IIIa (G PⅡb/Ⅲa),protease activated receptor-1 (PAR-1),protease activated receptor-4 (PAR-4); (3)the level of activated protein C(APC) and thrombus precursor pr otein (TpP);(4)the level of blood clotting, plasma thrombomodulin (TM) and D-dimer(D-D);(5)the level of tissue-type plasminogen activator(t-PA) and pl asminogen activator inhibitor(PAI);(6) the changes of hemorheolgy before an d after the modeling;(7)the level of Interleukelin-6(IL-6) and Interleukelin-8 (IL-8);(8)the level of Superoxide dismutase(SOD) and Malondialdehyde (M DA).
Results
General observation:Diffuse both lower limbs swelling of rabbits can be observed in all the three groups after modeling, while in OSE prevention gro up, swelling was significantly lesser than control group and OSE treatment gr oup. No significant swelling can be observed in the three groups when remo ving plaster on the 7th day later after modeling; however, the subcutaneous congestion areas were smaller in OSE prevention group than control group and OSE treatment group, while, one rabbit in the OSE treatment group and two rabbits in the model group died suddenly when we removed the plaster, it was confirmed that the reason of the death is Pulmonary embolism (PE). According to Zhao Xueling's method, it was reported that the percent of the successful models is 80%, and the data is similar with our pre-experimental result, even though no thrombosis formed, there is changes in the indicators of testing.
1. After the models were built, the level of CD62P、PAF and CD63 in the ser um of each group increased significantly, however, the level of CD62P、PDF and CD63 decreased in both OSE prevention group and OSE treatment group, compared with the control group. The prevention group was superior to the tre atment group
2. The level of serum GPⅡb/Ⅲa and PAR-1、PAR-4 increased in every group. The expression level of serum GP II b/IIIa and PAR-1、PAR-4 were signific antly decreased in OSE prevention group and OSE treatment group. Compared with treatment group, the prevention group was superior to the treatment group
3. After the models were built, the APC of the plasma in each rabbit reduced significantly, and the TpP increased significantly. Both the OSE prevention group and the OSE treatment group can increase the level of APC, and reduce the level of TpP. The result was statistically significant. And the prevention group was superior to the treatment group in each period.
4. Before building the models, in each group, there are no significant differen ces in the indicators of blood clotting, TM and D-D levels. And after the mod els were built, the influences to each evaluation indicators of the OSE prevent ion group were superior to the treatment group.
5. After the models were built, the serum level of t-PA were significantly decre ased, and the level of PAI increased significantly. Then in the seventh day, the level of serum t-PA were increased in OSE treatment group, while no signific ant changes of serum t-PA were detected in OSE prevention group, OSE treat ment group is better than OSE prevention group. The level of PAI in all phase in OSE prevention group were decreased significantly, the curative effect of w hich is better than OSE treatment group.
6. after the models were built, there is significant difference in the level of wh ole blood viscosity (ηb)、plasma viscosity (ηp)、RBC aggregation index (EAI) in the OSE prevention group, compared with the control group and the treatment group, while, there is significant difference in the treatment gro up on the seventh day, compared with the control group. The OSE prevention group were superior to the treatment group in each phase, there is no statistical significance in the change of EAI in each phase.
7. After the models were built, the IL-6,IL-8 level of each rabbits'serum incre ased significantly, while, both the OSE prevention group and the treatment gro up can reduce the IL-6,IL-8 level of rabbits'serum in the models. And there is no statistical significant difference in the result of each phase.
8. Before the experimental treatment, the SOD level of each serum dropped si gnificantly, the MDA level increased obviously. Compared with the control gr oup, there is statistical significance in the result of the OSE prevention group a nd the treatment group, and the prevention group was superior to the treatment group in each period
Conclusion:
The mechanisms of OSE which can prevent and treat traumatic DVT effectivly are following:(1).Hindering the activation of the platelet, reducing the expression of tissue factor, inhibiting platelet aggregation; (2).Inactivating coagulation factors, reducing the activity of the thrombin, ameliorating the hyper-coagulation state;(3).ameliorating fibrin lytic function, influencing the formation and degradation of fibrin, maintaining the normal fibrin lytic activity;(4).Ameliorating the state of blood flow, accelerating establishing collateral circulation, promoting the blood circulation; (5). Reducing the expression of the inflammation factors, increasing the coagulation inhibitory factors, preventing hyper-coagulation state;(6). scavenging oxygen free radicals, protecting endotheliocyte, and antioxidant.
This study shows that:(1)The main pathogenesis of "Thigh-Swollen" is blockage of phlegm and blood stasis -Yang qi failing to act freely is the key point, (2) About the treatment method of coexistence of phlegm and blood stasis, the method of activating yang is a vital treatment for "Thigh- Swollen",besides the method of reducing phlegm and removing blood stasis.(3) Through recovering and activating of the Yang-qi, which can reduce the damage of the pathological process, delay the cycle of illness aggravating, and make the pathological changes to the benign circulatio,and then, the function of each of the Zang-fu organs and meridians can be exertion normally. Yang-qi is "pungent warm", which can remove the phlegm and make the meridians act freely. Thus, Onion stalk extraction can be used for prevention and treatment on "Thigh- Swollen" which is also called DVT.
引文
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[2]黄新天,张培华.预防手术后深静脉血栓形成的进展.中华普通外科杂志,1998,13(5)：301.
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[4]邱贵兴,戴尅戎,杨庆铭等.预防骨科大手术后深静脉血栓形成的专家建议.中华骨科杂志,2005,25(10)：636-639.
[5]陆芸,马宝通,郭若霖.等.骨科创伤患者深静脉血栓危险因素的研究.中华骨科杂志,2007,27：693-698.
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