TLR4和VDR在2型糖尿病和糖尿病肾病尿毒症患者单核细胞的炎症调节作用及1，25-（OH）_2D3干预机制研究
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摘要
目的
2型糖尿病（T2DM）和糖尿病肾病（DN）尿毒症患者外周血CD14~+CD16~+单核细胞数和Toll样受体4（TLR4）在单核细胞的表达水平及相关细胞因子浓度的差异。
方法
对22例非DN尿毒症患者、30例DN尿毒症患者、28例单纯T2DM患者和20例健康志愿者外周血流式细胞术检测CD14~+CD16~+单核细胞数和TLR4在单核细胞的表达，免疫比浊法检测血清CRP水平，鲎试剂法检测血清内毒素水平，同时ELISA法检测外周血相关细胞因子IL-6和MCP-1的浓度。
结果
与正常对照组比较，T2DM组及DN尿毒症组外周血促炎CD14~+CD16~+单核细胞数及单核细胞TLR4和血清CRP水平均增高，且DN尿毒症组CD14~+CD16~+单核细胞数及单核细胞TLR4和血清CRP水平均较T2DM组显著增高。但非DN尿毒症组单核细胞TLR4表达较前三组均明显降低（P<0.01）。非DN尿毒症组CD14~+CD16~+单核细胞数和血清CRP水平均较DN尿毒症组稍低，但二者差异不明显（P>0.05）。四组相关细胞因子IL-6、MCP-1浓度逐渐升高，其中，DN尿毒症组>非DN尿毒症组> T2DM组>正常对照组，患者外周血CD14~+CD16~+单核细胞数及血清CRP水平与IL-6和MCP-1浓度呈正相关。2型糖尿病和尿毒症患者体内内毒素水平均较正常对照人群高，尤其以尿毒症患者浓度升高最明显（P<0.01）。
结论
以上结果提示在T2DM阶段就可能存在促炎CD14~+CD16`+单核细胞功能紊乱，这种功能紊乱可能参与了T2DM和DN尿毒症的发生发展。非DN尿毒症患者也存在单核细胞功能紊乱，但外周血炎症相关因子DN尿毒症患者较非DN尿毒症患者水平升高明显，这可能是DN为何跃升为终末期肾功能衰竭(ESRF)首位病因的原因之一。
目的
探讨1,25-(OH)_2D3及Toll-like recepter（TLR）4配体，脂多糖(Lipopolysaccharide，LPS)联合白介素（IL）-15对2型糖尿病（T2DM）和糖尿病肾病（DN）尿毒症患者血清干预的单核细胞维生素D受体（VDR）、TLR4、TLR9和STAT5、NF-κB信号通路及骨架蛋白表达的影响，进一步探索1,25-(OH)_2D3在T2DM和DN尿毒症炎症性免疫反应中的作用及其可能机制。
方法
分离研究对象（健康对照组20例、T2DM组28例和DN尿毒症组30例）外周血血清，孵育THP-1单核细胞，然后于含或不含1,25-(OH)_2D3培养液中培养，再用LPS和IL-15干预，干预结束后收集单核细胞和培养上清。采用实时荧光定量PCR检测VDR、TLR4、TLR9和IL-15的mRNA表达，Western blot检测THP-1单核细胞内TLR4、VDR、NF-κB P65、IκB、STAT5和p-STAT5蛋白表达。用ELISA法检测细胞培养上清IL-6和单核细胞趋化蛋白（MCP）-1水平，细胞免疫荧光和激光共聚焦等技术检测VDR和骨架蛋白的表达。然后通过STAT5抑制剂AG490干预后，检测LPS、IL-15及1,25-(OH)_2D3对T2DM、DN尿毒症患者血清诱导的THP-1细胞内STAT5磷酸化水平的影响。
结果
1.5％浓度的DN尿毒症患者血清对体外培养的THP-1细胞增殖有促进作用，且以12h作用最为显著，其机制可能与单核细胞上的TLR4有关。
2. LPS和IL-15干预后可下调T2DM和DN尿毒症患者血清孵育的单核细胞内VDR和IκB蛋白水平，上调TLR4、p-STAT5、NF-κB P65和IL-6、MCP-1蛋白及TLR4和IL-15mRNA水平，细胞骨架出现重排，各组TLR9mRNA和STAT5蛋白表达水平无显著性差异（P>0.05），而1,25-(OH)_2D3可部分阻断上述作用，1,25-(OH)_2D3提前干预后三组的VDR和TLR4mRNA表达及VDR、NF-κB P65、IκB和p-STAT5蛋白表达，以及相关炎症因子水平均无显著性差异（P>0.05），细胞形态和骨架蛋白分布均正常。
3.通过STAT5抑制剂AG490干预后，与LPS+IL-15组比较，VD3组、AG490+LPS+IL-15组和AG490+VD3组STAT5磷酸化水平均降低，具有显著性差异（P<0.01），其中以AG490+VD3组降低最明显。
结论
1,25(OH)2D3的抗炎机制可能与TLR4、NF-κB P65、VDR和STAT5信号途径及骨架蛋白有关。
目的
为了验证VDR和p-STAT5间的相互作用,进一步探索1,25-(OH)2D3在T2DM和DN尿毒症炎症性免疫反应中的作用及其可能机制。
方法
实验分3组：（1）对照组（2）LPS和IL-15干预组（3）1,25-(OH)_2D3提前干预组。先用免疫荧光对二者进行共定位。再用免疫共沉淀技术检测VDR和p-STAT5间的相互作用。
结果
LPS和IL-15干预组和1,25-(OH)_2D3提前干预组p-STAT5在胞核表达，较对照组明显增多，VDR和p-STAT5可结合在一起，且以1,25-(OH)_2D3提前干预组结合较前两组显著增多。
结论
单核细胞内VDR和p-STAT5可能存在相互作用。1,25-(OH)_2D3的抗炎机制可能是通过STAT5-VDR间的串话发挥作用，这种STAT5-VDR的串话作用可进一步解释了维生素D不足的患者为何易合并感染，对于维生素D不足易患人群（如DM和DN患者）及时、适量补充活性维生素D3，可能在DM和DN的防治方面具有一定的保护作用。
Aim
The differential expression of CD14~+CD16~+and TLR4expression inmonocytes and related cell factor levels among T2DM and DN uremiapatients.
Methods
Twenty-eight uremic patients without DN, thirty DN patients withuremia, twenty-eight T2DM patients, and twenty healthy volunteers wereenrolled for the determination of CD14~+CD16~+fluorescence intensity andTLR4expression on monocytes by using peripheral blood flow cytometry.Serum C-reactive protein (CRP) level was determined by using theimmunoturbidimetry. Serum endotoxin level was determined byquantitative colorimetric limulus test. Concentrations of IL-6and monocytechemoattractant protein-1(MCP-1) in supernatants were assessed by ELISA.
Results
Compared to normal control, T2DM patients and DN uremic patientshad a significantly higher CD14+CD16+fluorescence intensity, TLR4expression, and serum CRP level, whilst these biomarkers were moreupregulated in DN uremic patients than in T2DM patients.But thosebiomarkers were significantly downregulated in uremic patients withoutDN(P <0.01). Compared to uremic patients without DN, DN uremicpatients CD14+CD16+monocyte expression and serum CRP level wereslightly lower, but there were no significant differences (P>0.05).Concentrations of IL-6and MCP-1in supernatants were increasedgradually.And DN uremic patients> uremic patients without DN> T2DMpatients> normal control. Peripheral blood CD14~+CD16~+monocyteexpression，serum CRP level were increased and in a positive correlationwith supernatants IL-6and MCP-1concentrations.And the endotoxin（ET）levels were more upregulated in T2DM patients and uremic patientscompared to normal control, especially uremic patients had a significantlyhigher ET level(P <0.01).
Conclusion
These findings suggest that the immune disturbance inproinflammatory CD14~+CD16~+monocytes occurs at the stage of T2DM.Such immunological dysfunction may be mediated the occurrence and progression of T2DM and DN uremia. The monocytes dysfunction may bealso result in the occurrence of uremic patients without DN.However, DNuremic patients peripheral blood inflammation factors level were increasedsignificantly than in uremic patients without DN patients.It may be one ofthe reasons, which DN becomes the first one cause of end-stage renal failure(ESRF). To explore the effects of1,25-(OH)_2D3and lipopolysaccharide (LPS)plus human recombinant interleukin-15(IL-15) on expression of vitamin Dreceptor(VDR), Toll-like receptors4（TLR4）,TLR9, STAT5, NF-κBsignaling pathway and cytoskeletal rearrangement in human monocytesincubated with sera from type2diabetes （T2DM）patients and diabeticnephropathy（DN） patients with uremia. To further investigate its possiblemechanism of1,25-(OH)_2D3in T2DM and DN uremia inflammatoryimmune response.MethodsPeripheral sera were isolated from healthy volunteers (control group),T2DM patients and DN uremic non-dialysis patients. After incubation with or without1,25(OH)2D3, THP-1monocytes were treated with LPS plusIL-15prior to the collection of cells and supernatants.VDR, TLR4, TLR9and IL-15mRNA transcription was examined by Real-time PCR, whilstTHP-1monocytic TLR4, VDR, NF-κBP65, IκB, STAT5and p-STAT5expressions were investigated by Western blotting. Concentrations of IL-6and monocyte chemoattractant protein-1(MCP-1) in supernatants wereassessed by ELISA.Immunofluorescence and a laser confocal microscopywas used to examine the expression of VDR and cytoskeletal proteins. Todetect the effect of AG490on LPS, IL-15,1,25-(OH)_2D3and sera mediatedTHP-1monocytic STAT5phosphorylate level.
Results
1. The THP-1cells proliferation was promoted which incubated by the5%concentration serum of uremic patients with diabetic nephropathy invitro， and the most significant effect was12h group than the others, whichmechanism may be related to TLR4.
2. Compared to the normal control, LPS and IL-15down-regulatemonocytic VDR and IκB expression in T2DM patients and DN uremicpatients, whilst with cytoskeletal rearrangement,they up-regulate TLR4,p-STAT5, NF-κB P65protein expression as well as IL-6and MCP-1activityand TLR4, IL-15mRNA levels. However， there were no significantdifferences in TLR9mRNA and STAT5protein levels among the threegroups (P>0.05). Such effects could be in part blocked by1,25-(OH)_2D3. The aforementioned effects were improved following the pretreatment with1,25-(OH)_2D3. And there were no significant differences in VDR,TLR4mRNA and VDR,NF-κB P65,IκB and p-STAT5protein expression andrelated inflammation factors level of1,25-(OH)_2D3-treated THP-1monocytes on three groups (P>0.05). The cellular shape and the cytoskeletalproteins distribution were normal which on THP-1monocytes.
3. Prior to the pretreatment with AG490,compared to the LPS+IL-15group, VD3group,AG490+LPS+IL-15group and AG490+VD3group had asignificantly down-regulate THP-1monocytic STAT5phosphorylate level(P<0.01).And AG490+VD3group was the most remarkable.
Conclusion
The above results suggest that the anti-inflammatory mechanism of1,25-(OH)_2D3may be related to TLR4、NF-κB P65、cytoskeletal proteins,VDR and STAT5signaling pathway.
To validate the interaction between VDR and p-STAT5. And to furtherelaborate the potential mechanisms of immunoregulatory and anti-inflammatory effects of1,25-(OH)_2D3on T2DM and diabeticnephropathy（DN）patients with uremia.
Methods
The experiment divides into three groups（1）control group（2）LPSand IL-15-treated group（3）1,25-(OH)_2D3pretreated group. VDR andp-STAT5were co-localized by using immunofluorescence. As theimmunofluorescence experiment validated the possible intranuclearinteraction of VDR with p-STAT5, the immuno-coprecipitation and westernblotting assay of VDR was performed to further validate the interaction ofVDR with p-STAT5.
Results
Compared to the normal control, LPS+IL-15-treated group and1,25-(OH)_2D3pretreated group p-STAT5was expressed in the nuclei, VDRinteracted with p-STAT5, and1,25-(OH)_2D3pretreated group had asignificantly increasing.
Conclusion
Our results showed that VDR and p-STAT5possible to have interactionin the THP-1monocyte. The anti-inflammatory role of1,25-(OH)_2D3ininflammatory might be associated with STAT5-VDR cross-talk. Thiscross-talk might further explain why the vitamin D insufficient patient easyinfection,and the anti-inflammatory role of1,25-(OH)_2D3in inflammatoryand immune response of T2DM and DN might be associated with STAT5-VDR cross-talk. Therefore, the appropriate supplementation of1,25-(OH)_2D3might be prevention and protection for vitamine-D-deficientsubjects(such as DM and DN patients).
2型糖尿病（T2DM）和糖尿病肾病（DN）尿毒症患者外周血CD14~+CD16~+单核细胞数和Toll样受体4（TLR4）在单核细胞的表达水平及相关细胞因子浓度的差异。
方法
对22例非DN尿毒症患者、30例DN尿毒症患者、28例单纯T2DM患者和20例健康志愿者外周血流式细胞术检测CD14~+CD16~+单核细胞数和TLR4在单核细胞的表达，免疫比浊法检测血清CRP水平，鲎试剂法检测血清内毒素水平，同时ELISA法检测外周血相关细胞因子IL-6和MCP-1的浓度。
结果
与正常对照组比较，T2DM组及DN尿毒症组外周血促炎CD14~+CD16~+单核细胞数及单核细胞TLR4和血清CRP水平均增高，且DN尿毒症组CD14~+CD16~+单核细胞数及单核细胞TLR4和血清CRP水平均较T2DM组显著增高。但非DN尿毒症组单核细胞TLR4表达较前三组均明显降低（P<0.01）。非DN尿毒症组CD14~+CD16~+单核细胞数和血清CRP水平均较DN尿毒症组稍低，但二者差异不明显（P>0.05）。四组相关细胞因子IL-6、MCP-1浓度逐渐升高，其中，DN尿毒症组>非DN尿毒症组> T2DM组>正常对照组，患者外周血CD14~+CD16~+单核细胞数及血清CRP水平与IL-6和MCP-1浓度呈正相关。2型糖尿病和尿毒症患者体内内毒素水平均较正常对照人群高，尤其以尿毒症患者浓度升高最明显（P<0.01）。
结论
以上结果提示在T2DM阶段就可能存在促炎CD14~+CD16`+单核细胞功能紊乱，这种功能紊乱可能参与了T2DM和DN尿毒症的发生发展。非DN尿毒症患者也存在单核细胞功能紊乱，但外周血炎症相关因子DN尿毒症患者较非DN尿毒症患者水平升高明显，这可能是DN为何跃升为终末期肾功能衰竭(ESRF)首位病因的原因之一。
目的
探讨1,25-(OH)_2D3及Toll-like recepter（TLR）4配体，脂多糖(Lipopolysaccharide，LPS)联合白介素（IL）-15对2型糖尿病（T2DM）和糖尿病肾病（DN）尿毒症患者血清干预的单核细胞维生素D受体（VDR）、TLR4、TLR9和STAT5、NF-κB信号通路及骨架蛋白表达的影响，进一步探索1,25-(OH)_2D3在T2DM和DN尿毒症炎症性免疫反应中的作用及其可能机制。
方法
分离研究对象（健康对照组20例、T2DM组28例和DN尿毒症组30例）外周血血清，孵育THP-1单核细胞，然后于含或不含1,25-(OH)_2D3培养液中培养，再用LPS和IL-15干预，干预结束后收集单核细胞和培养上清。采用实时荧光定量PCR检测VDR、TLR4、TLR9和IL-15的mRNA表达，Western blot检测THP-1单核细胞内TLR4、VDR、NF-κB P65、IκB、STAT5和p-STAT5蛋白表达。用ELISA法检测细胞培养上清IL-6和单核细胞趋化蛋白（MCP）-1水平，细胞免疫荧光和激光共聚焦等技术检测VDR和骨架蛋白的表达。然后通过STAT5抑制剂AG490干预后，检测LPS、IL-15及1,25-(OH)_2D3对T2DM、DN尿毒症患者血清诱导的THP-1细胞内STAT5磷酸化水平的影响。
结果
1.5％浓度的DN尿毒症患者血清对体外培养的THP-1细胞增殖有促进作用，且以12h作用最为显著，其机制可能与单核细胞上的TLR4有关。
2. LPS和IL-15干预后可下调T2DM和DN尿毒症患者血清孵育的单核细胞内VDR和IκB蛋白水平，上调TLR4、p-STAT5、NF-κB P65和IL-6、MCP-1蛋白及TLR4和IL-15mRNA水平，细胞骨架出现重排，各组TLR9mRNA和STAT5蛋白表达水平无显著性差异（P>0.05），而1,25-(OH)_2D3可部分阻断上述作用，1,25-(OH)_2D3提前干预后三组的VDR和TLR4mRNA表达及VDR、NF-κB P65、IκB和p-STAT5蛋白表达，以及相关炎症因子水平均无显著性差异（P>0.05），细胞形态和骨架蛋白分布均正常。
3.通过STAT5抑制剂AG490干预后，与LPS+IL-15组比较，VD3组、AG490+LPS+IL-15组和AG490+VD3组STAT5磷酸化水平均降低，具有显著性差异（P<0.01），其中以AG490+VD3组降低最明显。
结论
1,25(OH)2D3的抗炎机制可能与TLR4、NF-κB P65、VDR和STAT5信号途径及骨架蛋白有关。
目的
为了验证VDR和p-STAT5间的相互作用,进一步探索1,25-(OH)2D3在T2DM和DN尿毒症炎症性免疫反应中的作用及其可能机制。
方法
实验分3组：（1）对照组（2）LPS和IL-15干预组（3）1,25-(OH)_2D3提前干预组。先用免疫荧光对二者进行共定位。再用免疫共沉淀技术检测VDR和p-STAT5间的相互作用。
结果
LPS和IL-15干预组和1,25-(OH)_2D3提前干预组p-STAT5在胞核表达，较对照组明显增多，VDR和p-STAT5可结合在一起，且以1,25-(OH)_2D3提前干预组结合较前两组显著增多。
结论
单核细胞内VDR和p-STAT5可能存在相互作用。1,25-(OH)_2D3的抗炎机制可能是通过STAT5-VDR间的串话发挥作用，这种STAT5-VDR的串话作用可进一步解释了维生素D不足的患者为何易合并感染，对于维生素D不足易患人群（如DM和DN患者）及时、适量补充活性维生素D3，可能在DM和DN的防治方面具有一定的保护作用。
Aim
The differential expression of CD14~+CD16~+and TLR4expression inmonocytes and related cell factor levels among T2DM and DN uremiapatients.
Methods
Twenty-eight uremic patients without DN, thirty DN patients withuremia, twenty-eight T2DM patients, and twenty healthy volunteers wereenrolled for the determination of CD14~+CD16~+fluorescence intensity andTLR4expression on monocytes by using peripheral blood flow cytometry.Serum C-reactive protein (CRP) level was determined by using theimmunoturbidimetry. Serum endotoxin level was determined byquantitative colorimetric limulus test. Concentrations of IL-6and monocytechemoattractant protein-1(MCP-1) in supernatants were assessed by ELISA.
Results
Compared to normal control, T2DM patients and DN uremic patientshad a significantly higher CD14+CD16+fluorescence intensity, TLR4expression, and serum CRP level, whilst these biomarkers were moreupregulated in DN uremic patients than in T2DM patients.But thosebiomarkers were significantly downregulated in uremic patients withoutDN(P <0.01). Compared to uremic patients without DN, DN uremicpatients CD14+CD16+monocyte expression and serum CRP level wereslightly lower, but there were no significant differences (P>0.05).Concentrations of IL-6and MCP-1in supernatants were increasedgradually.And DN uremic patients> uremic patients without DN> T2DMpatients> normal control. Peripheral blood CD14~+CD16~+monocyteexpression，serum CRP level were increased and in a positive correlationwith supernatants IL-6and MCP-1concentrations.And the endotoxin（ET）levels were more upregulated in T2DM patients and uremic patientscompared to normal control, especially uremic patients had a significantlyhigher ET level(P <0.01).
Conclusion
These findings suggest that the immune disturbance inproinflammatory CD14~+CD16~+monocytes occurs at the stage of T2DM.Such immunological dysfunction may be mediated the occurrence and progression of T2DM and DN uremia. The monocytes dysfunction may bealso result in the occurrence of uremic patients without DN.However, DNuremic patients peripheral blood inflammation factors level were increasedsignificantly than in uremic patients without DN patients.It may be one ofthe reasons, which DN becomes the first one cause of end-stage renal failure(ESRF). To explore the effects of1,25-(OH)_2D3and lipopolysaccharide (LPS)plus human recombinant interleukin-15(IL-15) on expression of vitamin Dreceptor(VDR), Toll-like receptors4（TLR4）,TLR9, STAT5, NF-κBsignaling pathway and cytoskeletal rearrangement in human monocytesincubated with sera from type2diabetes （T2DM）patients and diabeticnephropathy（DN） patients with uremia. To further investigate its possiblemechanism of1,25-(OH)_2D3in T2DM and DN uremia inflammatoryimmune response.MethodsPeripheral sera were isolated from healthy volunteers (control group),T2DM patients and DN uremic non-dialysis patients. After incubation with or without1,25(OH)2D3, THP-1monocytes were treated with LPS plusIL-15prior to the collection of cells and supernatants.VDR, TLR4, TLR9and IL-15mRNA transcription was examined by Real-time PCR, whilstTHP-1monocytic TLR4, VDR, NF-κBP65, IκB, STAT5and p-STAT5expressions were investigated by Western blotting. Concentrations of IL-6and monocyte chemoattractant protein-1(MCP-1) in supernatants wereassessed by ELISA.Immunofluorescence and a laser confocal microscopywas used to examine the expression of VDR and cytoskeletal proteins. Todetect the effect of AG490on LPS, IL-15,1,25-(OH)_2D3and sera mediatedTHP-1monocytic STAT5phosphorylate level.
Results
1. The THP-1cells proliferation was promoted which incubated by the5%concentration serum of uremic patients with diabetic nephropathy invitro， and the most significant effect was12h group than the others, whichmechanism may be related to TLR4.
2. Compared to the normal control, LPS and IL-15down-regulatemonocytic VDR and IκB expression in T2DM patients and DN uremicpatients, whilst with cytoskeletal rearrangement,they up-regulate TLR4,p-STAT5, NF-κB P65protein expression as well as IL-6and MCP-1activityand TLR4, IL-15mRNA levels. However， there were no significantdifferences in TLR9mRNA and STAT5protein levels among the threegroups (P>0.05). Such effects could be in part blocked by1,25-(OH)_2D3. The aforementioned effects were improved following the pretreatment with1,25-(OH)_2D3. And there were no significant differences in VDR,TLR4mRNA and VDR,NF-κB P65,IκB and p-STAT5protein expression andrelated inflammation factors level of1,25-(OH)_2D3-treated THP-1monocytes on three groups (P>0.05). The cellular shape and the cytoskeletalproteins distribution were normal which on THP-1monocytes.
3. Prior to the pretreatment with AG490,compared to the LPS+IL-15group, VD3group,AG490+LPS+IL-15group and AG490+VD3group had asignificantly down-regulate THP-1monocytic STAT5phosphorylate level(P<0.01).And AG490+VD3group was the most remarkable.
Conclusion
The above results suggest that the anti-inflammatory mechanism of1,25-(OH)_2D3may be related to TLR4、NF-κB P65、cytoskeletal proteins,VDR and STAT5signaling pathway.
To validate the interaction between VDR and p-STAT5. And to furtherelaborate the potential mechanisms of immunoregulatory and anti-inflammatory effects of1,25-(OH)_2D3on T2DM and diabeticnephropathy（DN）patients with uremia.
Methods
The experiment divides into three groups（1）control group（2）LPSand IL-15-treated group（3）1,25-(OH)_2D3pretreated group. VDR andp-STAT5were co-localized by using immunofluorescence. As theimmunofluorescence experiment validated the possible intranuclearinteraction of VDR with p-STAT5, the immuno-coprecipitation and westernblotting assay of VDR was performed to further validate the interaction ofVDR with p-STAT5.
Results
Compared to the normal control, LPS+IL-15-treated group and1,25-(OH)_2D3pretreated group p-STAT5was expressed in the nuclei, VDRinteracted with p-STAT5, and1,25-(OH)_2D3pretreated group had asignificantly increasing.
Conclusion
Our results showed that VDR and p-STAT5possible to have interactionin the THP-1monocyte. The anti-inflammatory role of1,25-(OH)_2D3ininflammatory might be associated with STAT5-VDR cross-talk. Thiscross-talk might further explain why the vitamin D insufficient patient easyinfection,and the anti-inflammatory role of1,25-(OH)_2D3in inflammatoryand immune response of T2DM and DN might be associated with STAT5-VDR cross-talk. Therefore, the appropriate supplementation of1,25-(OH)_2D3might be prevention and protection for vitamine-D-deficientsubjects(such as DM and DN patients).
引文
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