Molecular Mechanism of Electroacupuncture Regulating Cerebral Arterial Contractile Protein in Rats with Cerebral Infarction Based on MLCK Pathway / 中国结合医学杂志

OBJECTIVE@#To explore the effect of electroacupuncture (EA) intervention on the vasoconstriction of cerebral artery smooth muscle cells after cerebral infarction.@*METHODS@#Male Wistar rats were randomly divided into 3 groups by a random number table: the model group (n=24), the EA group (n=24), and the normal group (n=6). The model and the EA groups were divided into different time subgroups at 0.5, 1, 3, and 6 h after middle cerebral artery occlusion (MCAO), with 6 rats in each subgroup. MCAO model was established using intraluminal suture occlusion method. The EA group was given EA treatment at acupoint Shuigou (GV 26) instantly after MCAO for 20 min. The contents of cerebrovascular smooth muscle MLCK, the 3 subunits of myosin light chain phosphatase (MLCP) MYPT1, PP1c-δ and M20, as well as myosin-ATPase activity were detected using immunohistochemistry and Western blotting.@*RESULTS@#The overall expression level of the MYPT1 and PP1c-δ in the model group was significantly higher (P<0.01). After EA intervention, the 0.5 h group expression level was close to that of the normal group (P>0.05), and the other subgroups were still significantly higher than the normal group (P<0.01). After EA intervention, the expression level of each subgroup was significantly lower than the corresponding model group. There was a significant difference between the 0.5 and 1 h subgroups (P<0.01), while a difference was also observed between the 3 and 6 h subgroups (P<0.05). The dynamic change rule gradually increased with the prolongation of infarction time within 6 h after infarction.@*CONCLUSION@#EA intervention can inhibit contraction of cerebral vascular smooth muscle cells and regulate smooth muscle relaxation by regulating MLCK pathway.

Construction of a core outcome set in clinical research of acupuncture and moxibustion for treatment of adhesive capsulitis / 中国针灸

This study aims to construct the core outcome set for the clinical trials of adhesive capsulitis treated with acupuncture and moxibustion. Using systematic review, semi-structured interview, Delphi questionnaire survey, analytic hierarchy process and expert consensus meeting, the primary outcomes are obtained, i.e. local tenderness, pain degree during movement, range of motion, changes in range of motion, function score, and score of local symptoms of shoulder joint. The secondary outcomes are myofascial thickness, thickness of the inferior wall of the joint capsule, health status, activity of daily living, incidence of adverse events, laboratory indexes, vital signs, cost-effectiveness, total effective rate, and patient satisfaction. It is expected to provide a reference for the outcome selection in clinical trials and the generation of medical evidences in the treatment of adhesive capsulitis with acupuncture and moxibustion.

Effect of Electro-acupuncture on Vasomotor Symptoms in Rats with Acute Cerebral Infarction Based on Phosphatidylinositol System / 中国结合医学杂志

OBJECTIVE@#To investigate the effect of electro-acupuncture (EA) on vasomotor symptoms in rats with acute cerebral infarction, by observing the changes in the expression of factors related to the phosphatidylinositol (PI) system.@*METHODS@#Forty-two Wistar rats were randomly divided into 3 groups by a random number table: the control group (n=6), the model group (n=18) and the EA group (n=18). The EA group was given EA treatment at Shuigou (GV 26) instantly after modeling with middle cerebral artery occlusion (MCAO) method, while the model and control groups were not given any treatment. The degrees of neurological deficiency were evaluated using neurological severity scores (NSS) and the brain blood flow was evaluated by a laser scanning confocal microscope. Western blot analysis was conducted to detect the expression levels of G-protein subtype (Gq) and calmodulin (CaM). Competition for protein binding was conducted to detect the expression level of inositol triphosphate (IP3). Thin layer quantitative analysis was conducted to detect the expression level of diacylglycerol (DAG). The expression level of intracellular concentration of free calcium ion ([Ca@*RESULTS@#The NSS of the model group was significantly higher than the control group at 3 and 6 h after MCAO (P<0.01), while the EA group was significantly lower than the model group at 6 h (P<0.01). The cerebral blood flow in the model group was significantly lower than the control group at 1, 3 and 6 h after MCAO (P<0.01), while for the EA group it was remarkably higher than the model group at the same time points (P<0.01). The expressions of Gq, CaM, IP3, DAG and [Ca@*CONCLUSION@#EA treatment at GV 26 can effectively decrease the over-expression of related factors of PI system in rats with acute cerebral infarction, improve cerebral autonomy movement, and alleviate cerebral vascular spasm.

Research progress on mechanisms of bidirectional regulation of acupuncture / 中国针灸

Bidirectional regulation is one of the key function of acupuncture. The stimulator, mediator and receptor are the basis while the specificity of acupoints and the multi-target regulation of receptors receiving stimulation signals are the essential link of the bidirectional regulation of acupuncture. The possible mechanisms of bidirectional regulation of acupuncture are discussed in 4 aspects, i.e. homeostasis mechanism, stress reaction, central adaptive regulation and autonomic nerve regulation. Knowing the limitations of bidirectional regulation and exploring suitable researchmethods are proposed to be the key points in future researches.

Scalp acupuncture combined with suspension training for balance dysfunction in patients with stroke: a randomized controlled trial / 中国针灸

OBJECTIVE@#To explore the effect of scalp acupuncture combined with suspension training on balance ability and motor function in stroke patients with balance dysfunction.@*METHODS@#A total of 105 stroke patients with balance dysfunction were randomly divided into a combined group (35 cases, 2 cases dropped off), a scalp acupuncture group (35 cases, 3 cases dropped off) and a suspension training group (35 cases, 2 cases dropped off). The scalp acupuncture group was treated with scalp acupuncture at bilateral suboccipital lateral line, parietal midline, upper 1/5 line of anterior oblique line of parietal and temporal and line 1 of the parietal lateral line on the opposite side of hemiplegia. The suspension training group was treated with suspension training. The combined group was treated with suspension training at the same time of scalp acupuncture. All the treatment was given once a day, 30 min each time, 5 days a week, for a total of 6 weeks. The Berg balance scale (BBS) score, balance tester and Fugl-Meyer assessment (FMA) score were used to evaluate the motor function and balance ability before treatment, 3 and 6 weeks into treatment. The clinical efficacy was evaluated in the 3 groups.@*RESULTS@#The scores of BBS and FMA in each group at 3 and 6 weeks into treatment were higher than those before treatment (@*CONCLUSION@#Scalp acupuncture combined with suspension training could improve the balance ability and motor function in stroke patients with balance dysfunction, and the curative effect is better than simple scalp acupuncture and simple suspension training.

Selection of optimized treatment plan of acupuncture for lateral femoral cutaneous neuritis / 中国针灸

OBJECTIVE@#To select the optimized treatment plan of acupuncture for lateral femoral cutaneous neuritis by using multiple indexes decision-making method based on the clinical evidence.@*METHODS@#The randomized control trials (RCTs) regarding acupuncture for lateral femoral cutaneous neuritis in the CNKI database, CBM database, WANFANG database, VIP database, PubMed, Cochrane Library and Embase published before December 31, 2017 were comprehensively collected. The modified Jadad scale was used to evaluate the quality of the RCTs. Then the evaluation indexes were selected and the dimensions of evaluation indexes were standardized by using extreme difference transformation method. The weight of each index was determined by using relative comparison method and the standardized matrix was weighted. Thus, the ideal solution and the negative ideal solution were obtained, and the relatively degree of each treatment plan to the ideal solution was calculated to propose the optimized plan of acupuncture for lateral femoral cutaneous neuritis.@*RESULTS@#A total of 18 RCTs were included, the optimized plan of acupuncture for lateral femoral cutaneous neuritis was using thin fire needle to rapidly prick the abnormal skin region with fast needle insertion-withdrawal technique; the fire needle was applied repeatedly; intensive pricking to form a treatment area; the treatment was given once every 5 days.@*CONCLUSION@#Based on the current clinical evidence, the optimized plan of acupuncture for lateral femoral cutaneous neuritis is using thin fire needle to prick the abnormal skin region; the multiple methods of plum-blossom needling met the characteristic of lateral femoral cutaneous neuritis and is suitable for clinical selection. The main acupoints are points in the abnormal skin area or the acupoints in the foot- meridian and foot- meridian, combined with lumbar Jiaji (EX-B2) points.

Meta analysis and analytic hierarchy process-based intervention strategy research of acupuncture for primary depressive disorder / 中国针灸

<p><b>OBJECTIVE</b>To acquire the optimal intervention methods of acupuncture on primary depressive disorder (PDD) through high quality clinical evidences of acupuncture for PDD and analytic hierarchy process.</p><p><b>METHODS</b>Databases of domestic and international medical literatures were retrieved with computer. And high-quality clinical evidences on treatment of PDD with acupuncture were collected. Jadad scale evaluation was adopted to estimate the quality of evidences. RevMan 5.1 software was applied for Meta analysis and statistical appraisal on effect size. Analytic hierarchy process was utilized on acquired clinical evidences to construct the model and matrix to screen the optimal interevention method.</p><p><b>RESULTS</b>Fourteen researches were included. And the result of Meta analysis showed that no statistical differences could be found on clinical control rate, marked effectiveness rate, effective rate and the overall clinical effective rate between acupuncture and selective serotonin reuptake inhibitor (SSRIs). The combination of acupuncture and SSRIs could improve the clinical control rate and the overall clinical effective rate. And a 6-week intervention of electro-acupuncture combined with SSRIs was considered as the best intervention for the best overall effect.</p><p><b>CONCLUSION</b>Based on the present clinical evidences, a 6-week intervention of acupuncture combined with SSRIs is the best intervention on mild or moderate PDD, which can obviously enhance the clinical control rate and the overall clinical effective rate.</p>

Demographic characteristics of acupuncture outpatient based on clinical investigation / 中国针灸

<p><b>OBJECTIVE</b>The demographic characteristics of acupuncture outpatient in China is investigated so as to provide clinical evidence for the establishment of acupuncture indication.</p><p><b>METHODS</b>Clinical epidemiological table was adopted to do cluster multistage random sampling in 36 hospitals of 31 provinces (municipalities and autonomous regions) in 2008. The composition ratios of all indices were analyzed with SPSS 13.0 software. And trend analysis was carried out on the patient's demographic characteristics and the age distribution of clinical indications.</p><p><b>RESULTS</b>In the year 2008, 31 858 cases of out patients from 36 hospitals of 6 administrative regions were collected. There were totally 14 411 male patients (45.2%) and 17 447 (54.8%) female. The gender ratio of male and female was 82: 100. The average age of the patients was (50.6 +/- 17.7) years old. The number of patients over 45 years old was more obvious than groups of other ages (P<0.05). Age differences can be found in those 6 regions (P<0.05). Clinical symptoms varied according to different ages of the patients. Different characteristics of age distribution of acupuncture indications were held to exist (P=0.000).</p><p><b>CONCLUSION</b>At the present, differences of gender, age and region can be found in out patients of acupuncture clinic. And the result shows that the number of female patients is more than male, with a large proportion of patients over 45 years old. Differences of age distribution characteristics of acupuncture indications still exist, which is considered to have the relation with the dominate indications of acupuncture and aging of the population.</p>

Study on the efficacy graded-disease-spectrum of acupuncture and moxibustion by the fuzzy comprehensive evaluation techniques: musculoskeletal and connective tissue diseases / 中国针灸

The descriptive cross sectional surveys were carried out among the outstanding clinical physicians in the field of acupuncture and moxibustion by using the survey sampling. The fuzzy comprehensive evaluation techniques was applied to evaluate the opinions of clinical experts in the field of acupuncture and moxibustion in order to classify the spectrum of diseases related to the musculoskeletal and connective tissue. After the statistical analysis on sixty-four diseases with 104 subtypes, the spectrum of diseases were determined as grade I spectrum of diseases with 13 subtypes of diseases, grade II spectrum of diseases with 51 subtypes of diseases, grade III spectrum of diseases with 10 subtypes of diseases, and grade IV spectrum of diseases with 30 subtypes of diseases. The outcomes reveal that acupuncture and moxibustion therapy have been applied widely for musculoskeletal diseases and connective tissue related diseases.

Indications of acupuncture outpatient based on clinical investigation / 中国针灸

<p><b>OBJECTIVE</b>The present situation of clinical indications of acupuncture in China is investigated in this article which provides clinical evidence for the establishment of acupuncture indications.</p><p><b>METHODS</b>Out-patients of acupuncture departments of 31 Chinese provinces in the year 2008 were investigated through the method of cluster random sampling. And the analysis was made on diseases sorting and distribution based on Pareto principle and with EpiMap software.</p><p><b>RESULTS</b>Information of 31 858 out-patients of the first treatment from 36 hospitals were collected which referred to 368 diseases of 16 disease systems. Among them, there were 57 most commonly-encountered diseases, 60 commonly-encountered diseases and 251 rare diseases.</p><p><b>CONCLUSION</b>There are totally 368 acupuncture clinical indications at present according to the investigation with disproportional distribution in administrative districts. It is held that indications of acupuncture have high centralization degree. Thus, the populariza tion and promotion on application of acupuncture indications should be strengthened.</p>

Characteristics and superiorities of acupuncture medicine / 中国针灸

Four characteristics and five major superiorities of traditional Chinese acupuncture was expounded in this article. The four characteristics are (1) theoretical characteristic which focuses on meridians, acupoints, circulation of qi and blood; (2) effect mechanism of disease prevention and treatment based on external stimulation and internal regulation; (3) clinical diagnosis with the combination of differentiation of syndromes according to meridians and collaterals, zang-fu organs, eight principles and diagnosis based on acupoints; (4) technical characteristic of adoption of unique apparatus and special manipulations. The five superiorities are (1) diagnosis: simple, rapid and accurate; (2) technique: easy to study and manipulate; (3) therapeutic effect: quick and obvious effect, extensive indications; (4) safety: non-toxic and less side-effects; (5) cost: comparatively cheap. Thus, it is held that acupuncture should play a more important role in medical service system with unique Chinese characteristics.

Classification basis and train of thought of functional dyspepsia in disease menu of acupuncture / 中国针灸

<p><b>OBJECTIVE</b>To explore the classification basis of functional dyspepsia in disease menu of acupuncture, and to provide regular analyzing process for classification of other diseases.</p><p><b>METHODS</b>Taking the control group as the classification basis, and the 5-level literature classification of evidence based medicine as the estimation basis, literatures which complied with the inclusion criteria were examined according to the sequence from high level to low. Evidences of low levels were given up if support can be acquired from documents of high level.</p><p><b>RESULTS</b>Acupuncture is approved to be effective for intervention on functional dyspepsia. Compared to the international accepted medicines such as Cisapride and Motilium, regular acupuncture has better therapeutic effects and less side effects in improving the gastro-power and relieving discomfort sensations.</p><p><b>CONCLUSION</b>Functional dyspepsia pertains to grade I of disease menu of acupuncture.</p>

Modern documentary research on disease menu of acupuncture-moxibustion for mental and behavioral disorder / 中国针灸

<p><b>OBJECTIVE</b>Dominant disease menu of mental and behavioral disorder of acupuncture therapy was summarized and obtained in this article.</p><p><b>METHODS</b>Literatures on clinical treatment of mental and behavioral disorder with acupuncture were picked up from CBMdisc and CNKI during 1978 to 2007. Types of mental and behavioral disorder and report frequency of each disease treated with acupuncture were counted. And dominant diseases which were favorable to be treated with acupuncture were acquired through analysis and inductive method.</p><p><b>RESULTS</b>Twenty-nine diseases of mental and behavioral disorder are favorable to be treated with acupuncture which were mentioned in totally 1967 related documents. It is found that the number of reports of sleep disorder, depression, hysteria aphronesia, dementia and sexual disorder are ranked as the top five.</p><p><b>CONCLUSION</b>It is concluded that the preponderant diseases of mental and behavioral disorder treated by acupuncture are dementia, withdrawal syndrome, mental retardation, obsessive-compulsive disorder, sleep disorder, gastrointestinal neurosis (gastrointestinal disorders), depression, alcoholism and globus hystericus.</p>

Observation on therapeutic effect of herb-partitioned spread moxibustion for treatment of chronic nonspecific ulcerative colitis / 中国针灸

<p><b>OBJECTIVE</b>To compare therapeutic effects of herb-partitioned spread moxibustion and western medicine on chronic nonspecific ulcerative colitis.</p><p><b>METHODS</b>Sixty cases were randomly divided into a spread moxibustion group (n = 28) and a western medicine group (n = 32). The spread moxibustion group was treated with herb-partitioned spread moxibustion at lower limb around stomach meridian, abdomen region around Guanyuan (CV 4) and lower Jiaji (EX B 2) points; and the western medicine group was treated with oral administration of Sulfasalazine. Their therapeutic effects were observed after treatment.</p><p><b>RESULTS</b>The cured-markedly effective rate was 71.4% (20/ 28) in the spread moxibustion group, and 25.0% (8/32) in the western medicine group, the former was better than the latter (P < 0.05).</p><p><b>CONCLUSIONS</b>The therapeutic effect of herb-partitioned spread moxibustion for treatment of chronic nonspecific ulcerative colitis is better than that of the oral administration of Sulfasalazine with less adverse reaction, and is worth popularizing in clinic.</p>

Spectrum of ocular and adnexal disease treated with acupuncture / 中国针灸

Data studies are adopted to do systematic analysis on diseases described in theses on effect observation of acupuncture in Chinese Bio-Medical Literature and Retrieval System during 1978 to 2005. Numbers (frequency) of the disease mentioned are counted so as to analyze the acupuncture spectrum of ocular and adnexal diseases. The result indicates that the number of acupuncture spectrum of ocular and adnexal diseases is 31, which includes 22 diseases and 5 symptoms defined with western medicine as well as 4 syndromes of TCM. Thus, it can be concluded that ocular and adnexal disease is the one of the major component of acupuncture spectrums, and it is worth to popularize and apply that acupuncture for illness of this kind in clinic.

Survey clinical evidence of acupuncture therapy for depressive neurosis / 中国针灸

<p><b>OBJECTIVE</b>To evaluate the clinical studies of acupuncture for treatment of depressive neurosis, collect the high quality evidence relative to clinical acupuncture practice for clinical decision-making reference.</p><p><b>METHODS</b>Around crucial common questions of acupuncture clinical practice, the documents of clinical study were comprehensively retrieved. According to 5-grade criterion of evidence-based medicine, the evidence from high to low level were selected to answer corresponding clincal questions and RevMan 5.0.20 was used to analyze the final indicator.</p><p><b>RESULTS</b>Nineteen documents of clinical study accord with the inclusive criterion were retrieved. Level-A evidence showed effectiveness of acupuncture. Acupuncture might be superior or equal to fluoxetine, with little adverse effect and high safety. Level-C evidence showed acupuncture might be superior or equal to Amitriptyline, with little adverse effect and high safety. And no relative clinicial evidence compared effect of acupuncture with that of psychotherapy or behavior therapy. Only one level-C evidence showed there was no effect difference between acupuncture combined with bloodletting therapy and bloodletting alone. Two level-C evidence showed the effect of acupuncture combined with western medicine was superior to that of medicine alone, eg. catgut embedding therapy combined with Fluoxetine, electroacupuncture combined with Seroxat.</p><p><b>CONCLUSION</b>Acupuncture for depressive nerosis has a positive effect. Acupuncture has an equal effect compared with western medicine, while strictly designed equivalent and non-inferior studies are demanded. The effect of acupuncture combined with medicine has some advantage, but need high quality studies to verify.</p>

Evaluation of therapeutic effect and safety for clinical randomized and controlled trials of treatment of acne with acupuncture and moxibustion / 中国针灸

<p><b>OBJECTIVE</b>To evaluate the therapeutic effect and safety of acupuncture and moxibustion for treatment of acne, and to analyze the current situation of clinical studies at present.</p><p><b>METHODS</b>Retrieve PubMed, Cochrane library, CBM databank, CNKI databank, etc., and collect the randomized and controlled trials of treatment of acne with acupuncture and moxibustion, and select clinical trials conforming with the enrolled criteria, and conduct evaluation of quality with Cochrane systematic manual 5.0, and RevMan 4.2.8 was used for statistical analysis.</p><p><b>RESULTS</b>Seventeen papers, including 1,613 cases, conformed with the enrolled criteria. Seventeen studies adopted the cured rate as the evaluation index, Meta-analysis showed treatment of acne by acupuncture and moxibustion with routine western medicine as control, significant difference for inter-group comparison [combined RR (random efficacy model) = 2.96, 95% CI (1.63, 4.91), Z=4.08. P<0.0001]; comprehensive acupuncture and moxibustion therapy was controlled with single acupuncture moxibustion therapy, significant difference for inter-group comparison [combined RR (fixed efficacy model) = 2.51, 95% CI (1.76, 3.57), Z=5.11, P<0.00001].</p><p><b>CONCLUSION</b>Acupuncture-mox ibustion is safe and effective for treatment of acne, and it is possibly better than routine western medicine, and the comprehensive acupuncture-moxibustion therapy is better than single acupuncture-moxibustion therapy. The conclusion has not been determined yet, because lower quality of a part of literature enrolled.</p>

Preliminary study on disease menu of acupuncture and moxibustion abroad / 中国针灸

Sum up clinical diseases and symptoms treated by modern acupuncture and moxibustion and disease menu of acupuncture and moxibustion abroad. By literature research methods, the diseases and symptoms reported in clinically acupuncture and moxibustion randomized controlled paper from 1978-2007 in databank of Pubmed network, USA, were analyzed and summarized, and the number of paper (frequency-times) and conclusion of therapeutic effect (effective and ineffective) of each disease reported were counted up. Five hundred and eighty-seven papers of clinical acupuncture and moxibustion abroad, including 130 diseases and symptoms of 16 systems, were found. In these papers, 110 diseases and symptoms were unanimously considered effective and 16 diseases and symptoms were considered effective by most papers, and one disease was showed by equal number of paper of positive or negative effect, and one disease was considered ineffective by most of the paper, and 2 diseases and symptoms were considered ineffective by all of the papers. It is indicated that acupuncture and moxibustion have wide indications and have been widely applied at home and abroad, and disease menu of acupuncture and moxibustion is enlarging, and acupuncture and moxibustion have a vast application prospects.

Assessment of methodology and report quality of systematic evaluation and meta-analysis of acupuncture-moxibustion in China / 中国针灸

<p><b>OBJECTIVE</b>To assess the methodology and report quality of systematic evaluation and Meta-analysis of acupuncture and moxibustion in China.</p><p><b>METHODS</b>Retrieve CBM, CNKI, WF and VIP database, collect data from the information system established by Epidata 2.1, assess the methodology and report quality by using the QQAQ and QUOROM, calculate the percentage of adequate rate.</p><p><b>RESULTS</b>Thirty-eight reviews, including twenty six systematic evaluation and twelve Meta-analyses, met the enrolled criteria. Twenty-two kinds of diseases and six diseases systems were included. The methodology quality scores were generally low (3.34 +/- 1.44). The causes of the problems were insufficient literature resource, bias in data collections and inaccurate merging methods. The report quality was relatively low in abstracts, methods, trial flow, introduction and data merging.</p><p><b>CONCLUSION</b>The amount of literatures on systematic evaluation and Meta-analysis of acupuncture is gradually increasing from 2002. However, the quality control is not ideal. It is important to improve the methodology and report quality.</p>

Systematic evaluation of the randomized controlled trials about acupuncture and moxibustion treatment of allergic rhinitis / 中国针灸

<p><b>OBJECTIVE</b>To evaluate the clinical effect and safety of acupuncture and moxibustion treatment for allergic rhinitis and to analyze the present situation of clinical researches.</p><p><b>METHODS</b>A search in PubMed, Cochrane Library, Chinese Biology Medicine (CBM) disk, and China National Knowledge Infrastructure (CNKI) databases was performed to gather the randomized controlled trials about acupuncture and moxibustion treatment for allergic rhinitis, identify additional clinical trials met the inclusion criteria and measure their qualities by using Cochrane Reviewers' Handbook 5.0. Statistical analysis was carried out by RevMan 4.2.8.</p><p><b>RESULTS</b>A meta-analysis was performed on a total of 1076 patients involved in 12 papers which met the inclusion criteria. There were significant differences in both cure rate (Incorporate RR = 1.86, 95% CI 1.51, 2.29, Z = 5.82, P < 0.00001) and marked improvement rate (Incorporate RR = 1.58, 95% CI 1.32, 1.89, Z = 4.94, P < 0.00001) between acupuncture and moxibustion treatment and the routine medicine treatment for allergic rhinitis.</p><p><b>CONCLUSION</b>Acupuncture and moxibustion to treat allergic rhinitis is effective and safe and may have certain advantage over the routine medicine treatment. However, as for the low quality of partial inclusion literatures, no definite conclusion can be obtained as yet and it still waits for higher quality researches to further prove the dominance of acupuncture and moxibustion treatment for allergic rhinitis.</p>