电针对慢性内脏痛大鼠脊髓背角降钙素基因相关肽的影响

目的:检测电针对慢性内脏痛大鼠脊髓背角内降钙素基因相关肽(calcitonin gene-related peptide,CGRP)表达的影响。方法:SD大鼠随机分成正常对照组,慢性内脏痛模型组和模型加电针组,每组6只。慢性内脏痛模型采用新生幼鼠结直肠刺激方法制备;模型加电针组选取双侧"足三里"和"上巨虚",疏密波,强度1mA,持续30min,隔日一次,持续四次。记录结直肠扩张刺激下腹外斜肌放电幅值;免疫组织化学法检测各组大鼠胸腰段、腰骶段脊髓背角内CGRP的表达变化。结果:电针能够显著降低内脏痛大鼠结直肠扩张刺激诱导的腹外斜肌放电幅值(P0.05);免疫组织化学染色法显示:CGRP样免疫阳性物质的表达在模型组大鼠的胸腰段、腰骶段脊髓背角内均显著升高(P0.01),而模型加电针组的胸腰段、腰骶段脊髓背角内CGRP的表达与模型组相比有显著降低(P0.01)。结论:电针降低慢性内脏痛敏反应的镇痛机制与减少脊髓背角内CGRP样免疫阳性物质的表达有关。     

电针刺激对炎性痛大鼠脊髓背角小胶质细胞活化的影响

目的:探索电针(EA)刺激是否通过下调糖原合成酶激酶3β(GSK3β),抑制小胶质细胞活化缓解大鼠慢性炎性痛。方法:利用完全随机数字法将Sprague Dawley (SD)雄性大鼠分为对照组(control)、完全弗氏佐剂注射组(CFA)、CFA+电针刺激组(CFA+EA)和CFA+GSK3β抑制剂TDZD-8组(CFA+TDZD-8)。通过足底注射CFA方法制备大鼠炎性痛模型,利用电针刺激和给予不同的药物处理各组大鼠。采用经典von Frey丝检测各组大鼠机械缩足反射阈值(PWT),用Western Blot法或免疫荧光检测脊髓背角GSK3β和小胶质细胞离子钙接头蛋白(Iba-1)表达的变化情况。结果:与control组相比,CFA组大鼠在各时间节点的PWT值均显著降低(P <0.01);脊髓背角中GSK3β和Iba-1表达明显增加(P <0.05)。与CFA组相比,CFA+EA组大鼠PWT显著升高(P <0.01),GSK3β和Iba-1表达量显著下调(P <0.05); CFA+TDZD-8组大鼠PWT显著升高(P <0.01),Iba-1的表达量...     

High-frequency electroacupuncture versus carprofen in an incisional pain model in rats

The objective of the present study was to compare the effect of electroacupuncture (EA) and carprofen (CP) on postoperative incisional pain using the plantar incision (PI) model in rats. A 1-cm longitudinal incision was made through skin, fascia and muscles of a hind paw of male Wistar rats and the development of mechanical and thermal hypersensitivity was determined over 4 days using the von Frey and Hargreaves methods, respectively. Based on the experimental treatments received on the third postoperative day, the animals were divided into the following groups: PI+CP (CP, 2 mg/kg, po); PI+EAST36 (100-Hz EA applied bilaterally at the Zusanli point (ST36)); PI+EANP (EA applied to a non-acupoint region); PI+IMMO (immobilization only); PI (vehicle). In the von Frey test, the PI+EAST36 group had higher withdrawal force thresholds in response to mechanical stimuli than the PI, PI+IMMO and PI+EANP groups at several times studied. Furthermore, the PI+EAST36 group showed paw withdrawal thresholds in response to mechanical stimuli that were similar to those of the PI+CP group. In the Hargreaves test, all groups had latencies higher than those observed with PI. The PI+EAST36 group was similar to the PI+IMMO, PI+EANP and PI+CP groups. We conclude that 100-Hz EA at the ST36 point, but not at non-acupoints, can reduce mechanical nociception in the rat model of incisional pain, and its effectiveness is comparable to that of carprofen.     

电针对内脏痛模型大鼠结肠壁、背根节和脊髓内AchE和CGRP表达的影响

目的:观察电针治疗内脏痛对结肠壁、背根节和脊髓内胆碱酯酶(AchE)和降钙素基因相关肽(CGRP)免疫阳性物质表达的影响,以探讨AchE和CGRP免疫阳性物质在痛觉传递中的作用及电针镇痛的机制。方法:26只SD大鼠随机分为正常对照组(6只)、内脏痛组(VP组,10只)和电针+内脏痛组(EA+VP组,10只)。电针取双侧"足三里"穴刺激60 min,运用酶组织化学技术和免疫组织化学技术,观察电针刺激对福尔马林所诱发的大鼠盆腔内脏痛时,结肠壁、背根节和脊髓内AchE和CGRP免疫阳性物质表达的影响。结果:内脏痛组大鼠在注射福尔马林后,结肠壁、背根节和脊髓内AchE免疫阳性物质的表达显著高于正常组(P<0.01),CGRP免疫阳性物质的表达显著低于正常组(P<0.01);而电针+内脏痛组,结肠壁、背根节和脊髓内AchE免疫阳性物质的表达显著低于内脏痛组(P<0.01),CGRP免疫阳性物质的表达又显著高于内脏痛组(P<0.01)。结论:电针对大鼠急性盆腔内脏痛具有预防性治疗作用,Ach和CGRP可能参与了电针对内脏痛的调节作用。     

Spinal cholinergic mechanism of the relieving effects of electroacupuncture on cold and warm allodynia in a rat model of neuropathic pain

This study was performed to determine whether spinal cholinergic systems mediate the relieving effects of electroacupuncture (EA) on cold and warm allodynia in a rat model of neuropathic pain. For neuropathic surgery, the right superior caudal trunk was resected at the level between the S1 and S2 spinal nerves innervating the tail. Two weeks after the injury, the intrathecal (i.t.) catheter was implanted. Five days after the catheterization, the rats were injected with atropine (non-selective muscarinic antagonist, 30 μg), mecamylamine (non-selective nicotinic antagonist, 50 μg), pirenzepine (M₁ muscarinic antagonist, 10 μg), methoctramine (M₂ antagonist, 10 μg) or 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP) (M₃ antagonist, 10 μg). Ten minutes after the injection, EA was applied to the ST36 acupoint for 30 min. The cold and warm allodynia were assessed by the tail immersion test [i.e., immersing the tail in cold (4°C) or warm (40°C) water and measuring the latency of an abrupt tail movement] before and after the treatments. The i.t. atropine, but not mecamylamine, blocked the relieving effects of EA on cold and warm allodynia. Furthermore, i.t. pirenzepine attenuated the antiallodynic effects of EA, whereas methoctramine and 4-DAMP did not. These results suggest that spinal muscarinic receptors, especially M₁ subtype, mediate the EA-induced antiallodynia in neuropathic rats. J. H. Park and S. K. Kim have contributed equally to this work.     

电针足三里对慢性不可预见性抑郁症大鼠多器官损伤的作用及其机制

目的:探讨电针足三里对慢性不可预见性应激大鼠多内脏器官损伤的作用。方法:将雄性SD大鼠随机分为5组:正常对照组(对照组)、慢性应激组(应激组)、慢性应激非经非穴电针刺激组(非穴组)、慢性应激足三里电针刺激组(足三里组)和慢性应激氟西汀治疗组(氟西汀组)。采用慢性不可预见性应激法造模后,非穴组和足三里组给予电针刺激,氟西汀组给药,每天1次3周;经Open-field行为测试,解剖观察、H-E染色和免疫组化法等进行统计学分析。结果:与应激组相比,足三里组和氟西汀组大鼠的行为明显改善;应激组大鼠出现胃腺和食管黏膜上皮萎缩,肺出现灶状充血,肺组织间炎症细胞增多,20%～30%出现肺脓肿现象;足三里组和氟西汀组胃腺、食管黏膜上皮和肺组织病变减轻,未见肺脓肿发生,5-羟色胺(5-HT)免疫反应增强,阳性细胞数目增多;足三里组与应激组相比具有显著性差异。结论:电针足三里对慢性不可预见性抑郁症大鼠多器官损伤具有改善作用,其机制可能与电针的刺激效应,调节了神经通路,并促进了周围器官的5-HT合成有关。     

Analgesic effect of electroacupuncture on complete Freund's adjuvant-induced inflammatory pain in mice: a model of antipain treatment by acupuncture in mice

Electroacupuncture (EA) was applied bilaterally to the acupoints of Zu-san-li (ST-36) and Kun-lun (BL-60) in the hindlimbs of mice. The therapeutic effect of EA on inflammatory pain induced by an ipsilateral injection of complete Freund's adjuvant (CFA) into the right paw of the mouse was investigated in this study. The time of paw-withdrawal latency (PWL) was used as an indicator for judging the intensity of the pain induced by the CFA injection. The EA effects were divided into immediate (PWL tests within 2 h after EA treatment) and cumulative (PWL tests during and after repetitive EA treatments for 3 weeks) effects. As immediate effects, PWL was significantly shortened in the CFA-injected paw, but was again prolonged 20 min after an EA treatment and lasted until 30 min after. As cumulative effects, PWL was significantly shortened in the CFA-injected paw, but recovered from the 2nd to the 8th day during repetitive EA treatments. No such effects could be observed after sham EA treatment, which resulted in behavior similar to that in untreated animals. These results demonstrate that the CFA-induced inflammatory pain in mice is an ideal model system for the investigation of EA effects and may serve as a valuable reference for the clinical treatment of inflammatory pain in human beings. Furthermore, the mouse pain model opens the possibility to apply the investigation also to transgenic mice.     

miR-146a在大鼠神经病理性疼痛模型中的表达及其作用机制

目的 研究miR-146a对神经病理性疼痛的调控机制.方法 将大鼠随机分为:1)na(i)vve组(n=12);2)假手术组(n=12):进行大鼠双侧假手术;3)双侧慢性压迫损伤(bCCI)组(n=12):建立大鼠双侧坐骨神经结扎模型.在建模前1d及后第1、3、7和14天监测机械刺激诱发痛、热刺激诱发痛行为学指标;实时定量PCR法检测背根神经节(L4-L6) miR-146a及TNF-α受体相关因子6(TRAF6)、白介素1受体相关激酶(IRAK1)的mRNA表达水平;Western blot法检测TRAF6及IRAK1蛋白表达.结果 bCCI大鼠双足热刺激诱发痛痛阈、机械刺激诱发痛痛阈较na(i)ve组、假手术组显著降低(P＜0.05).术后第14天bCCI组miR-146a表达水平较na(i)ve组显著下降(P＜0.05).bCCI组TRAF6、IRAK1的mRNA表达水平较na(i)ve组升高(P ＜0.05);TRAF6、IRAKI蛋白表达水平较假手术组和na(i)ve组均显著增加(P＜0.05).结论 神经病理性疼痛大鼠背根神经节miR-146a表达水平下调,miR-146a可能通过过度激活其靶基因TRAF6和IRAK1发挥作用.     

An in-silico model of the biosynthesis of neurotransmitter glutamate, elucidates the complex regulatory role of glucocorticoids in neurotransmitter glutamate release

An in-silico model, of the glucocorticoid regulated glutamate release, in rat hippocampal tissue, is constructed. The model permits the pseudo-steady state estimation of various fluxes, experimentally impossible to measure, from a set of measured rates. Estimates of the astrocytic pyruvate carboxylase reaction and the neuronal TCA cycle rates are correlated with different dexamethasone concentrations, in order to extrapolate explicit kinetic equations. The model suggests that the observed effects of glucocorticoids can be attributed to the inhibitory actions of dexamethasone on two competing pathways, that of the neuronal TCA cycle and the biosynthetic pathway of neurotransmitter glutamate.     

Mechanism of pain in osteoid osteomas: an immunohistochemical study

Osteoid osteoma is a benign bone tumour characterized by pain which is relieved by non-steroidal anti-inflammatory drugs (NSAIDs), such as aspirin. To clarify the mechanism of the pain, five osteoid osteomas were studied immunohistochemically using polyclonal antibodies against prostaglandin E2 (PGE2), S-100 protein and protein gene product 9.5 (PGP 9.5). In all five cases, the pain had been relieved by NSAIDs. Nerve fibres positive for S-100 protein and PGP 9.5 were observed in the fibrous zone, especially close to the blood vessels, around the nidus in all the lesions and also within the nidus in three lesions. PGE2 immunoreactivity was variably positive in the nidus of three lesions. In one case a large number of actively proliferating osteoblasts reacted with this antibody. The other cases showed unevenly distributed PGE2 positivity which tended to be prominent in the plump osteoblasts. As control material we examined fibrous dysplasia (3 cases), osteosarcomas (3) and giant-cell tumours of bone (3). The plump osteoblastic tumour cells of three osteosarcomas and the bone-forming cells in two cases of fibrous dysplasia gave a positive reaction for PGE2. No S-100 or PGP 9.5 immunoreactive nerve fibres were seen in these lesions. It is concluded that the presence of nerve fibres alone might play a more important role in mediation of pain in osteoid osteomas than some effects of osteoblast-produced PGE2 on the nerves and proliferated blood vessels.     

Neurosensory changes in a human model of endothelin-1 induced pain: a behavioral study

Although pain is a frequent feature in patients with cancer, its etiology is still poorly understood. In recent years, endothelin-1 (ET-1) has become a major target molecule in the etiology of cancer pain. In this randomised, double-blind study the effects of intradermal injection of ET-1 on spontaneous pain, temperature perception and sensation of punctate stimulation were evaluated. Thirty-five subjects were randomised to receive either placebo or one of four concentrations of ET-1 (ranging from 10(-10) to 10(-6)M). Besides assessment of spontaneous pain, three neurosensory testings were performed: (1) cold and warm sensation, (2) cold and heat pain, and (3) punctate stimulation using a von Frey monofilament. ET-1 produced a dose-dependent flare zone that was absent after placebo injection. Subjects reported a short-lasting spontaneous pain upon administration of the highest concentrations of ET-1. Injection of ET-1 induced a long-lasting and dose-dependent punctate hyperalgesia in an area around the injection site (secondary hyperalgesia). Thermal testing revealed a short period of hypoesthesia to non-noxious warm and cold stimuli after some doses of ET-1. In addition to the mechanical hyperalgesia, intradermal injection of ET-1 almost instantaneously induced a state of cold hyperalgesia outlasting the study period (120 min). No development of heat hyperalgesia was observed. The observed psychophysical characteristics of this new model of ET-1 induced nociception indicate its potential as a human experimental model for cancer pain.     

海洛因成瘾复吸大鼠脑组织超微结构和部分神经递质的变化

目的：建立海洛因成瘾、脱毒,复成瘾、脱毒,再成瘾、脱毒3个阶段大白鼠模型,了解海洛因致各阶段大白鼠脑损害的动态趋势。方法：电镜下观察脑超微结构变化,荧光分光度法测定脑NA、DA、5-HT等神经递质的含量。结果：3个阶段大鼠脑内多部位神经元胞体、轴突、树突都出现变性、凋亡、胀亡等超微病理结构改变,神经胶质细胞、神经毯也出现相应的超微病理结构改变,而且随复吸次数增多而病变加重。脑NA、DA、5-HT、含量升高,而且随复吸次数增多而升高。结论：大白鼠脑组织出现广泛性超微病理结构改变,随复吸次数增多而病变加重,脑神经递质含量也随复吸次数增多而升高。     

骨癌痛外周机制研究进展

癌痛是临床晚期恶性肿瘤患者最常见的症状之一，也是破坏患者生活质量的重要因素。近年来出现的各种骨癌痛模型，为深入研究骨癌痛机制、寻找新的治疗方法提供了契机。骨癌痛具有复杂的发病机制。随着肿瘤的生长和骨质的破坏，病灶中与肿瘤相关的诸多因子不断释放（如前列腺素、内皮素、神经生长因子等），在肿瘤局部构成复杂而独特的微环境，持续激活并敏化支配骨组织的伤害性感受器。在骨癌痛发展的过程中，交互存在着炎症反应、神经损伤及其他组织损伤等病理变化，导致伤害性刺激传入信息增加，引起剧烈的疼痛     

Impact of an Arthritis Self-Management Programme with an added exercise component for osteoarthritic knee sufferers on improving pain, functional outcomes, and use of health care services: An experimental study

OBJECTIVE: The aim of this study was to assess the effect of an adopted Arthritis Self-Management Programme (ASMP) with an added exercise component among osteoarthritic knee sufferers in Hong Kong. METHODS: An experimental study with 88 participants assigned to an intervention group and 94 participants to a control group. One hundred and forty-nine participants (81.9%) completed the 1 week and 120 participants (65.6%) the 16 week post-intervention assessments. Participants in the intervention group received a 6-week ASMP with an added exercise component. Outcome measures included arthritic pain and fatigue rating, practice of light exercise routines, functional status, and number of unplanned arthritis-related medical consultations. To assess the programme's effect on outcome measures, the between-groups and within-group mean changes were compared using Mann-Whitney U-test and Friedman test. RESULTS: At 16 weeks, there were significant mean changes between groups in four outcome measures: reduction in arthritis pain (p=0.0001) and fatigue (p=0.008), and increased duration of weekly light exercise practice (p=0.0001) and knee flexion (p=0.004). The ability to perform daily activities and the number of unplanned arthritis-related medical consultations show statistically significant improvements between three time-points within the intervention group only (p=0.0001 and p=0.005, respectively), but not between-groups (p=0.14 and p=0.86, respectively). Both groups apparently had no changes in muscle strength. CONCLUSION: Our findings suggest that the intervention had a positive effect in reducing pain, fatigue, knee range of motion, the practice of exercise routines, the number of medical consultations and in improving functional status and over a 16-week period. PRACTICE IMPLICATIONS: The self-management programme we applied took into account the local context and the ethnicity of the group. This process is worth further exploration and testing in different groups.     

Analgesic effects of antiepileptic drugs in a pain syndrome of spinal origin

A pain syndrome of spinal origin was induced by the formation of a generator of pathologically enhanced excitation (GPEE) in the dorsal horns of the lumbosacral segments of the rat spinal cord by means of disinhibitors (tetanus toxin, strychnine, penicillin) and depolarizers (KCl and ouabain), applied to one side of the dorsal surface of the spinal cord in a 1% agar wafer. The investigations showed that the analgesic action of the anticonvulsants was determined by the nature of the GPEE thus formed. Diphenylhydantoin had no significant effect on the development of pain syndromes induced by disinhibitors but abolished those due to the action of depolarizers. Carbamazepine abolished pain syndromes associated with the formation of a GPEE by depolarizers, lengthened the latent period of appearance of the syndrome following the formation of a GPEE by tetanus toxin, shortened the duration of the pain syndrome produced by a strychnine generator but did not abolish the syndrome produced by a penicillin generator. Seduxen had a similar action to carbamazepine and the depth of the effect depended on dose, Phenazepam, a new Soviet tranquilizer, had a stronger action than seduxen. It is concluded that the activity of a generator located in the nociceptive system and the spread of pathologically enhanced excitation produced by the generator over this system can be inhibited by means of antiepileptic drugs, and in that way a pain syndrome of spinal origin can be abolished. The results are in agreement with the theory of the generator mechanisms of central pain syndromes.Laboratory of General Pathology of the Nervous System, Institute of General Pathology and Pathological Physiology, Academy of Medical Sciences of the USSR, Moscow. Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 88, No. 8, pp. 147–151, August, 1979.     

Analgesic effects of inhibitory mediators in a pain syndrome of spinal origin

A pain syndrome of spinal origin was induced by creating a generator of pathologically enhanced excitation (GPEE) in the dorsal horn of the lumbosacral segments of the spinal cord in rats with the aid of tetanus toxin, strychnine, penicillin, KCl, and ouabain. The substances were applied to the dorsal surface of the spinal cord. An agar wafer method was developed to enable local prolonged and dose-dependent effects of the substances applied to be produced and studied in freely behaving animals. The effects of the inhibitory mediators were determined by the nature of the generator produced and, in particular, by the state of the mediator-receptor system of the neuronal membranes of cells forming in GPEE. Glycine prevented the development of the pain syndrome in the case of generators induced with tetanus toxin, penicillin, KCl, and ouabain. GABA was effective in the case of generators produced by tetanus toxin, potassium, and ouabain. Injection of glycine into the region of a generator produced by tetanus toxin at the height of development of the pain syndrome abolished that syndrome for the duration of action of the mediator. The pain syndrome could thus be specifically abolished or prevented for the period of action of the mediator by depressing the GPEE with the appropriate inhibitory mediators, depending on the nature of the GPEE, i.e., on the features distinguishing the state of the mediator apparatus of its neurons. Under these conditions inhibitory mediators, although not analgesics in the pharmacological sense, have a specific analgesic effect.Laboratory of General Pathology of the Nervous System, Institute of General Pathology and Pathological Physiology, Academy of Medical Sciences of the USSR, Moscow. Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 87, No. 6, pp. 525–528, June, 1979.     

改良NBAS-APS在肝胆外科术后镇痛中的应用研究

目的评价改良的以护士为基础、以麻醉医师为指导的疼痛管理模式（NBAS-APS）在肝胆外科术后疼痛管理中应用的效果。方法406例患者随机分为3组，分别为传统疼痛管理模式组（C-APS）、NBAS-APS模式组和改良的NBAS-APS模式组（NBASS—APS），对三组术后患者进行随机的观察性研究，进行疼痛评分并观察镇痛效果。结果与传统的疼痛管理模式比较，NBAS-APS和改良的NBAS—APS模式的术后止痛效果指标（VAS值）显著降低，术后24h和48h的睡眠时间显著增加，患者总体满意度显著提高，且改良的NBAS—APS模式又优于NBAS—APS模式。结论NBAS—APS可显著提高术后镇痛效果，改良的NBAS—APS模式更优于NBAS—APS，更加适合临床实际。     

Endoscopic Facet Debridement for the treatment of facet arthritic pain - a novel new technique

Study design: Retrospective, observational, open label.Objective: We investigated the efficacy of facet debridement for the treatment of facet joint pain.Summary of background data: Facet joint disease, often due to degenerative arthritis, is common cause of chronic back pain. In patients that don''t respond to conservative measures, nerve ablation may provide significant improvement. Due to the ability of peripheral nerves to regenerate, ablative techniques of the dorsal nerve roots often provide only temporary relief. In theory, ablation of the nerve end plates in the facet joint capsule should prevent reinnervation.Methods: All patients treated with endoscopic facet debridement at our clinic from 2003-2007 with at least 3 years follow-up were included in the analysis. Primary outcome measure was percent change in facet-related pain as measured by Visual Analog Scale (VAS) score at final follow-up visit.Results: A total of 174 people (77 women, 97 men; mean age 64, range 22-89) were included. Location of facet pain was cervical in 45, thoracic in 15, and lumbar in 114 patients. At final follow-up, 77%, 73%, and 68% of patients with cervical, thoracic, or lumbar disease, respectively, showed at least 50% improvement in pain. Mean operating time per joint was 17 minutes (range, 10-42). Mean blood loss was 40 ml (range, 10-100). Complications included suture failure in two patients, requiring reclosure of the incision. No infection or nerve damage beyond what was intended occurred.Conclusions: Our results demonstrate a comparable efficacy of endoscopic facet debridement compared to radiofrequency ablation of the dorsal nerve branch, with durable results. Large scale, randomized trials are warranted to further evaluate the relative efficacy of this surgical treatment in patients with facet joint disease.     

大鼠开胸术后慢性疼痛的预测指标

目的观察疼痛时弥散性伤害抑制性控制(DNIC)的动态变化,对术前DNIC、术后急性疼痛能否作为术后慢性胸痛的预测指标进行初步研究。方法术前检测大鼠DNIC,建立开胸术后慢性疼痛模型,分组为空白组(n=10)、假手术组(n=10)、模型组(n=20),连续监测术后1、3、6、9、12、15、18和21 d的机械痛阈、冷痛阈及DNIC。结果模型组大鼠中,11只发展为慢性疼痛组(CPTP组),9只在经历急性疼痛后痛觉恢复正常(non-CPTP组)。与CPTP组比较,non-CPTP组术前DNIC减弱(P0.05),术后6 d切口附近机械痛阈值及冷痛阈值更低(P0.05)。与术前DNIC相比,模型组术后急性疼痛时期(术后3 d)DNIC减弱(P0.05),CPTP组术后21 d DNIC持续减弱(P0.05),而non-CPTP组DNIC恢复正常。结论术前DNIC及术后6 d急性疼痛程度是开胸术后慢性疼痛的两项危险因素;疼痛急性期,个体DNIC减弱,痛觉恢复正常时,个体DNIC水平也渐趋恢复正常。