On retrouve fréquemment des paresthésies (fourmillements,

On retrouve fréquemment des paresthésies (fourmillements, Compound Library cell line engourdissements) et/ou des dysesthésies (fourmillements, engourdissements ou picotements perçus comme désagréables). La douleur a une topographie neurologique systématisée, fonction de la lésion anatomique causale. L’examen clinique objective un trouble de la sensibilité superficielle dans la région douloureuse (hypoesthésie cutanée au tact ou à la piqûre, voire anesthésie complète localisée), éventuellement associé à une allodynie, une hyperalgésie, une hyperpathie (encadré 1). Le diagnostic est principalement clinique. Le questionnaire DN4 (disponible en complément électronique) est un outil

diagnostique essentiel et simple d’utilisation : click here validé en 2005 [7], il est basé sur des caractéristiques douloureuses recueillies à l’interrogatoire et sur des données d’examen clinique. Un score supérieur ou égal à 4/10 établit une forte probabilité de douleur neuropathique. Allodynie Douleur causée par un stimulus qui normalement ne produit pas de douleur ; elle peut être de différents types : • tactile ou mécanique : – à l’effleurement

cutanée : allodynie dite dynamique Hyperalgésie Réponse exagérée à un stimulus qui normalement est douloureux Hyperpathie Syndrome douloureux caractérisé par une réaction anormalement douloureuse below à un stimulus (en particulier un stimulus répétitif), avec extension du champ récepteur Hyperesthésie Sensibilité exagérée à une stimulation (terme moins utilisé, à abandonner) On citera les douleurs aiguës nociceptives consécutives à un geste invasif diagnostique ou thérapeutique (biopsies, myélogrammes, ponctions veineuses, ponctions lombaires, injections intraveineuses, sous-cutanées …), les douleurs induites itératives (pansements, sondage urinaire, soins, toilette …), les douleurs postopératoires d’exérèse tumorale et les séquelles chirurgicales douloureuses après mastectomie, thoracotomie, curage ganglionnaire ou après prostatectomie radicale, amputation

du rectum etc. À ces douleurs s’ajoutent les douleurs post-chimiothérapie liées aux médicaments cytotoxiques, responsables de mucites (avec surinfections fréquentes), de neuropathies périphériques sensitivomotrices (où la toxicité et la douleur sont dose-dépendantes et de réversibilité variable). Parmi les douleurs post-radiothérapie, on retrouve des mucites, des radiodermites douloureuses (moins fréquentes qu’auparavant), des ostéoradionécroses (notamment en cancérologie ORL), des plexites radiques (brachiale ou lombo-sacrée) après irradiation cervicale ou axillaire ou bien lombopelvienne, des myélites radiques, des atteintes viscérales radiques pouvant toucher différents organes comme l’œsophage, la vessie, le grêle, le rectum.

Moreover Reppas, Usrey and Reid

Moreover Reppas, Usrey and Reid selleckchem (Reppas

et al., 2002) found saccadic eye movements modulated LGN responses to flickering fields of uniform intensity in awake, behaving macaques. In a similar study, Saul (Saul, 2010) found that saccades changed the response times of neurons. These results show that anesthetizing the animal changes the nature of neuronal responses, especially how they might respond to natural scenes and naturalistic noise. In a similar technical convention that has constrained results, nearly all experiments have used annular stimuli (Alitto and Usrey, 2008, Babadi et al., 2010, Solomon et al., 2006 and Solomon et al., 2002) with a limited ability to fully examine the detailed spatial structure and extent of the ECRF. Non-uniformity of an annular structure in the ECRF has been reported (Webb et al., 2005), but a rigorous, definitive mapping has not yet been performed. Contemporary stimulus generation systems are able to present full-field arbitrary stimuli at high refresh rates, and contemporary computers are readily capable of analyzing large volumes of data

(Alivisatos et al., 2012 and Briggman and Bock, 2012) created by extensive stochastic stimuli. Further experiments in alert primates responding to natural stimuli that address these gaps in the current body of work are needed to better understand the visual system and its properties, and the technical and analytic tools to do so are now available. In this paper we have gathered current knowledge of selleck compound primate LGN receptive fields, classical and extra-classical, to illuminate the areas that need more work to achieve a better understanding. Much less is known about ECRFs, their source, shape, and how they behave in response to stimuli, than CRFs. Most of the studies that have involved LGN mapping concentrate on the CRF, and few have examined the ECRF. Just as there is more known about CRFs than ECRFs, there is more work mafosfamide done using artificial stimuli than with natural stimuli. Because most of the work

done has been with artificial stimuli, it is hard to know if the field is inadvertently missing important factors involved in visual processing that are present when natural stimuli are used. Technological advancement in stimulus generation and data analysis provide the opportunity to study the ECRF and the CRF in greater detail. Coupled with the growing appreciation of the importance of conscious influence on early sensory processing, the field could see a shift toward using natural stimuli in awake animals for a fuller understanding of the visual system. Despite the tremendous advances in the half-century since Hubel and Wiesel’s initial work, there remains much left to learn about the early visual pathway.

The substitute question for the Tampa Scale for Kinesiophobia was

The substitute question for the Tampa Scale for Kinesiophobia was introduced with the sentence, You visited your general practitioner because of complaints in your back or leg, followed by the question How much ‘fear’ do you have that these complaints would be increased by physical activity? (scores range from 0 = no fear, to 10 = very much fear). Disability: The Roland Morris Disability Questionnaire for sciatica is a validated measurement for disability ( Patrick et al 1995, Roland & Morris 1983). It contains 24 questions that can be answered with ‘yes’ or ‘no’. The substitute question for the

Roland Morris Disability Questionnaire PD0325901 in vitro was, In your normal daily activities, how much trouble do you have from your back or leg complaints? (scores range from 0 = no trouble, to 10 = maximal trouble). Health-related quality of life: The EQ-5D is a validated measurement of health outcome ( Lamers et al 2006, The EuroQol Group 1990). The EQ-5D was developed by the EuroQol group and consists of 5 questions on mobility, self care, usual activities, pain/discomfort, and anxiety/depression, with

3 answer categories. A weighted sum results in a score in the range –0.3 to 1, with higher scores indicating better health status. The SF-36 is a validated questionnaire to survey health status ( Aaronson et al 1998, Ware and Sherbourne 1992). It contains 36 questions, each with 2 to 5 response options. The SF-36 has no overall score, but two summary scores can be calculated: a physical component summary and a mental Obeticholic Acid component summary. Because of a large overlap, we created one substitute question for both the EQ-5D and the SF-36 physical component summary. This substitute question was, How would

you rate your general health? (scores range from 0 = excellent, to 10 = very poor). Outcome measures were global perceived effect and pain severity in the leg at 1 year follow-up. Assessment of the outcome measures was done using a mailed questionnaire to be filled out by each participant. Thalidomide Global perceived effect was measured on a 7-point scale ranging from 1 = completely recovered, to 7 = vastly worsened. Global perceived effect is regarded as a clinically relevant, reliable, and responsive outcome measure (Bombardier 2000, Dworkin et al 2005). We dichotomised the ratings into ‘recovered’ (‘completely recovered’ and ‘much improved’) and ‘not recovered’ (‘slightly improved’ to ‘worse than ever’) (Luijsterburg et al 2008). Pain severity in the leg was scored on an 11-point numerical rating scale ranging from 0 = no pain, to 10 = unbearable pain (Von Korff et al 2000). A numerical rating scale is regarded as a clinically relevant, reliable, valid, and responsive pain scale (Dworkin et al 2005). Missing values in the original trial database were imputed by assigning the last available score. Our research question was answered by calculating correlations and applying logistic regression models.

Importantly, LC–MS revealed a number of different adulterants tha

Importantly, LC–MS revealed a number of different adulterants that were mixed to cocaine: Fig. 1B shows a representative chromatogram. Among others we found paracetamol, benzoylecgonine, levamisole and phenacetin (Table 1); levamisole was present in almost two thirds of all examined samples (66 of 104 samples). The Veliparib purchase ratio between cocaine and levamisole in these samples was highly variable. While some samples contained less than 1% levamisole, one sample even

displayed 20 times more levamisole than cocaine. The mean amount of levamisole was 59 ± 22% relative to cocaine. This highly variable amount of the different drugs also emphasize the risk incurred: people consume the purchased drug until they experience the desired effect (Cole et al., 2010). Hence, they are likely to also consume more of the adulterant. Given the fact that in our survey levamisole was the most commonly used adulterant of cocaine, we reasoned that it likely has pharmacological properties that render it especially useful as adulterant. This conjecture is justified, because our findings are in line with other reports: levamisole has been observed to be one of the most predominant adulterants over the past two decades (Buchanan et al., 2010 and Chai et al., 2011). Hence, we first explored whether levamisole exerted

an action on the three main neurotransmitter transporters SERT, NET and DAT using HEK293 cells

stably expressing the individual human isoforms ABT-263 nmr of these transporters. Uptake-inhibition experiments were performed with increasing concentrations of levamisole or cocaine (Fig. 2). Cocaine blocked the uptake at the expected concentrations (Ravna et al., 2003): the observed IC50 values were 1.8 ± 1.12 μM (SERT), 1.0 ± 1.07 μM (NET) and 0.56 ± 1.12 μM (DAT). Levamisole also reduced the uptake of substrate but at much higher concentrations. Measured IC50 values were 1512 ± 1.09 μM (SERT), 74.5 ± 1.12 µM (NET), 209.9 ± 1.31 μM (DAT). Based on the high IC50 values of levamisole, it is unlikely that the compound exerts mafosfamide any significant inhibitory action on the transporters in vivo, when administered in therapeutic doses (e.g., as an adjuvant in cancer chemotherapy). Oral administration of 50 mg levamisole gives rise to peak plasma concentrations (cmax) of on average 368 μg/L (equivalent to about 1.5 μM) ( Gwilt et al., 2000). There is a large intraindividual variation in pharmacokinetics ( Gwilt et al., 2000) and some uncertainty about nasal absorption. In addition, levamisole is a highly lipophilic substance that readily permeates the blood–brain barrier ( Lin and Tsai, 2006). Therefore levamisole may possibly reach higher concentrations than cocaine in the brain and thereby lead to or support a blockage of NET and DAT, when consumed at excessive levels.

Other notable examples of differences between crude and weighted

Other notable examples of differences between crude and weighted strain prevalence were seen in 2000–2003 in the European, American, and African regions and in the Eastern Mediterranean region in 2004–2007. The imminent introduction of RV vaccines in immunization programs worldwide prompted us to review regional and temporal trends in rotavirus strain diversity globally in the pre-vaccine selleck screening library era. Over the 12-year period from 1996 to 2007, we compiled information on ∼110,000 RV strains, including over 70,000 strains from 5 years

immediately preceding vaccine introduction that have not been previously reviewed. Overall, this study represents the most comprehensive systematic review of global RV strain prevalence, and the findings provide important baseline data and insights to help understand and evaluate the impact of RV vaccination programs. First, the range of circulating RV strains differed across regions during the same time period, and predominant strains within a single check details location or country changed over time, often year-by-year. This complexity of RV strain diversity is thought to be driven by genetic drift of the neutralizing antigens and by reassortment of cognate (including replacement of neutralization antigen) genes

among locally co-circulating strains. Moreover, importation of strains from a different area and zoonotic transmission of animal strains could also increase the genetic diversity of human rotaviruses in many areas [10] and [11]. The natural variability in rotavirus strains over time is important to consider when evaluating temporal changes in RV strains following introduction of vaccines, as they could potentially be mistakenly attributed to the effects of the vaccine program. Indeed, the click here predominance of fully heterotypic

G2P[4] strains in Brazil after the introduction of the monovalent G1P[8] rotavirus vaccine has generated much debate in the scientific community, and it is still not known if this phenomenon is related to vaccine use or reflects natural variation in strain prevalence [11] and [38]. Second, the medically most important 4 G types and 2 P types first detected during the 1980s (G1P[8], G2P[4], G3P[8], and G4P[8]) remained common during the 1990s and 2000s, and were predominant in numerous temperate zone countries [8], [9] and [39]. However, since the mid 1990s additional potentially important G and P types and numerous new antigen combinations have been documented, with rapid spread of 2 novel antigen combinations, G9P[8] and G9P[6], globally. Similarly, the occurrence of G12 strains, mainly combined with P[6] or P[8] VP4 gene, have been reported from at least 30 countries since their rediscovery in 1998 [11], and in many locations these strains were identified at a frequency comparable to other common endemic strains.

DK and OT are employees of HealthCore, Inc SB has received a sin

DK and OT are employees of HealthCore, Inc. SB has received a single honorarium from MedImmune for the development of an educational presentation. Contributors: Study concept and design: EA and CA Acquisition of data: DK, OT, and EA. Analysis and interpretation of data: all authors. Drafting of the manuscript and critical revision of the manuscript for important intellectual content: EA, DK, and CA and critical review and editing of the manuscript: all authors. Statistical analysis: DK and EA. All authors approved the final manuscript for submission.

Financial disclosures: EA was an employee of MedImmune, Gaithersburg, MD when the study was conducted and manuscript written. CA and HC are employees of AstraZeneca, the parent company Selleck NU7441 of MedImmune, Gaithersburg, MD and may have stock or stock options. DK and OT are employees of HealthCore, Inc. SB has received a single honorarium from MedImmune for the development of an educational presentation. Funding support: This research was funded by MedImmune. Role of the sponsor: Drs. Ambrose, and Caspard are employees

of AstraZeneca, the parent company of MedImmune. MedImmune funded the study, therefore, the role of the sponsor included study design, collection, analysis, and interpretation of data, writing the report, and the decision to submit the article for publication. Additional contributions: Editorial assistance was provided by Susan E. HDAC inhibitor DeRocco, PhD, and John E. Fincke, PhD, of Complete Healthcare Communications, Inc. (Chadds Ford, PA) and funded by MedImmune. “
“Vaccination is the cornerstone of the global public health strategy to mitigate an eventual influenza pandemic. Rapid production of vaccine to immunize billions of people in a short period of time requires development Cell press of alternative manufacturing platforms, such as large-scale animal cell culture bioreactors. In combination with other methods, cell-based manufacturing would augment vaccine manufacturing capacity to respond to a pandemic [1]. MDCK and VERO cell culture–derived influenza vaccines have

received regulatory approval in some countries [2] and [3]. Influenza vaccines produced in cell cultures have relied on candidate vaccine viruses developed by the WHO GISRS laboratories for vaccine production in embryonated eggs [4]. Although these viruses are ideal for the traditional method of vaccine production in eggs, the growth can be suboptimal for production of vaccines in cell cultures [4]. A sustainable supply of circulating influenza viruses isolated in cell cultures that meet regulatory requirements would be required to support cell-based vaccine manufacturing. Critical information on the comparative performance of several regulatory requirement-compliant cell lines for isolation of influenza viruses from clinical species for subsequent use as candidate vaccine viruses is not available.

26 NS-EA 51 successfully prevented the histaminic effects on gast

26 NS-EA 51 successfully prevented the histaminic effects on gastric juice volume, pH, acid-output, ulcer formation and pepsin activity in the PL rats (Table 1). Additionally, it inhibited gastric ulcer formation induced by hypothermic-restrained stress (Table 2). However, the fraction did not alter significantly gastric mucus secretions in the rats having either histamine plus PL or hypothermic and restraint stress-induced gastric ulcers (Table 1 and Table 2). Famotidine, a reference drug also caused similar anti-ulcer effects in the experimental animals. But

data pointed out clearly, NS-EA 51 to be the stronger anti-ulcer agent in comparison to the Famotidine (Table 1 and Table 2). The above presented data, has suggested that the purified fraction under experiment lacks any cytoprotective activity and its anti-ulcer DAPT molecular weight effects might be caused by the inhibition of gastric aggressive factors i.e. acid and pepsin which is also in accordant to our previous report. 9 Famotidine, a well-established check details H2-receptor antagonist showed anti-ulcer effects in both histaminic plus PL

and hypothermic-restrained stress models due to the inhibition of gastric histaminic receptors. Therefore, it may be speculated that the fraction may interfere with the histaminic pathway like Famotidine. It is conceivable; therefore, that the mechanism of anti-ulcerogenic action of NS-EA 51, i.e. attenuation of the effects of histamine on gastric juice volume, pH, acid out-put, ulcer index and pepsin activity as well as inhibition of the effect of hypothermic-restraint stress on ulcer index in addition

to the lipid peroxidation prevention, 9 could possibly be related to its interference with the histaminic pathway. In conclusion, the reported results have validated the anti-ulcer activity of the NS-EA 51 fraction isolated from NS. Further pharmacological investigations are still required to elucidate the precise mode(s) of anti-ulcer actions. All authors have none to declare. The authors would like to thank the Islamia University of Bahawalpur-PAKISTAN for provision of research facilities. “
“A homoisoflavanone, (3R)-5,7-dimethoxy-(4′-hydroxybenzyl)-4-chromanone Adenylyl cyclase of the compound (R)-5, was previously isolated from Scilla nervosa (Burch.) Jessop 1 as well as from Drimiopsis burkei Bak. 2 The traditional use of S. nervosa for rheumatic fever indicates possible anti-inflammatory properties of its constituents. 3 Subsequent studies showed strong inhibition of prostaglandin synthesis in microsomal cells by the isolated homoisoflavanone, supporting the traditional use of S. nervosa. 4 Studies indicate that stereoselectivity plays an important role in the anti-inflammatory activities of non-steroidal anti-inflammatory drugs. 5 The decision to employ either a racemate or a pure enantiomer for therapeutic purposes is usually based on the diverse mechanisms of actions of the enantiomers.

Because of the sign

Because of the Pomalidomide poor return rate for the exercise diaries, we were unable to assess the adherence of experimental group participants with their exercise program. While the physiotherapy intervention for the experimental group included thoracic cage mobility exercises, we did not attempt to assess thoracic cage mobility because of the complexity of doing so and the extensive range of outcome measures already being performed. While assessors were blinded, participants were aware of whether or not they received physiotherapy intervention, introducing a potential source of bias. Medical and nursing staff were not informed of participants’ group allocations,

but it is acknowledged that this may have become apparent to them and influenced their care. As all participants received a booklet preoperatively, this, and their

consent to participate in a study, may have resulted in a Hawthorne effect. Despite every effort to maximise retention (ie, repeated attempts to contact non-responders, scheduling outpatient follow-up appointments after work hours or to coincide with surgical unit outpatient appointments), loss to follow-up was fairly high, particularly at 3 months, which may have biased our Selleck Duvelisib results. Further research should be undertaken in other centres to attempt to confirm our findings and to further refine the clinical importance of the treatment effects. Research to evaluate the effect of a similar postoperative exercise program on thoracic cage mobility and chronic incisional pain after open thoracotomy would also be worthwhile. Whilst a formal cost benefit analysis was not performed, the costs associated with the physiotherapy interventions provided

to experimental group participants across their hospital stay were minimal and, arguably, appeared to be of clinical benefit. Future research to formally quantify costs is recommended. Additionally, research could be undertaken to evaluate whether the provision of a formal out-patient rehabilitation program for patients following discharge after open thoracotomy would increase functional benefits DNA ligase and quality of life. eAddenda: Appendix 1, 2, and 3, and Table 4 available at www.JoP.physiotherapy.asn.au Ethics: The Northern X Regional Ethics Committee, New Zealand, approved this study. Participants gave written informed consent before data collection began. Support: The New Zealand Society of Physiotherapists, Greenlane Research and Educational Fund, the New Zealand Cardiothoracic Physiotherapy Special Interest Group and the Auckland DHB Charitable Trust Fund. The authors wish to thank: patients involved in the study; Cardiothoracic Surgical Unit staff; Susan Preeti Anil, Jasmine Kershaw, Winifred Ho and Rachel Wheeler who acted as blinded assessors; and Elizabeth Tulley and Steve White for their advice on shoulder measurement.

arjuna in an unbiased and unmanipulated

arjuna in an unbiased and unmanipulated INCB024360 mw form. This study is an inference of pooled data from 1208 patients suffering from one or the other forms of cardiac problems visiting the Ramakrishna Charitable dispensary Rajahmundry since 2 years. Details collected from the outpatient ticket and echocardiography registry record section of Ramakrishna Charitable dispensary Rajahmundry included patient demographics, cardiac symptoms, respiratory symptoms, echocardiographic evaluations data, treatment summaries, emergency hospital visits and any mortalities. Diagnosis were based on proper guidelines

for heart failure concomitant with dilated cardiomyopathy by experts in the field who visited the hospital. Complete information of individual patients was created from the time of problem inception to till date. Prescription data of cardiovascular drugs were collected along with the status of the symptoms. Finally 93 patients were included in the study who fulfilled all the

inclusion and exclusion criteria and had similar baseline characteristics including the disease period. The patients visiting Staurosporine datasheet this hospital usually comprises of population from neighbouring rural areas who have a tendency to depend on Indian medicinal plants. Apart from the modern medicine, patients who were on regular treatment with T. arjuna capsules (standardized bark extract) from

the ayurvedic section for any heart complaints were included in the study. Dilated cardiomyopathy (NYHA II, III), coronary artery disease with LV dysfunction (ECG/ECHO) may be present. Treatment with either or both modern medicine and T. arjuna capsules 500 mg tid. Primarily valvular heart disease with dilated cadiomyopathy, post-cardiac transplant cardiomyopathy, peripartum cardiomyopathy, tachycardiomyopathy, Congenital heart disease with left ventricular dysfunction, chronic lung and advanced kidney or liver diseases. Patients were grouped according to the treatment they were receiving for dilated cardiomyopathy of idiopathic or ischaemic in origin. In addition all those patients on T. arjuna medication for cardiac disease with heart failure were identified and grouped accordingly. these Baseline characteristics like number of patients for each treatment group, mean age of patient in each group, history of smoking, diabetes, hypertension and other risk factors were noted in a tabular form. Treatment for heart failure was based on individual symptoms and therefore nonspecific for the groups. Echocardiography (2D, M-mode and Doppler imaging) was performed using the GE Voluson 3 MHz probe. The following undermentioned parameters were measured according to the professional standards defined by the American society of echocardiography.

0001), IgG1 (p < 0 0001), IgG2a (p < 0 0001),

IgG2b (p = 

0001), IgG1 (p < 0.0001), IgG2a (p < 0.0001),

IgG2b (p = 0.0094) and IgG3 (p = 0.0003) but not for IgA (p = 0.5164) or IgM (p = 0.0783) antibodies. As disclosed before challenge, the IgG1 and the IgM antibodies were strongly enhanced by all the saponins ( Fig. 2). In the case of IgM, a significant enhancement was also noted after infection Saracatinib in the saline controls. Following the R saponin positive control, the CA4 saponin raised more IgG and IgG2a antibodies to the FML antigen than the CA3 saponin ( Fig. 2). Indeed, the average absorbance of CA4 increased from 0.564 before to 1.189 after infection (p = 0.0079) while the average for CA3 vaccinated mice did not significantly changed (from 0.718 to 0.689; p = 0.114). Furthermore, the CA4sap vaccine IgG2a response after infection was not statistically different from the saponin R vaccine. All saponins raised equivalent levels of IgG1 above the saline control and only the R saponin significantly enhanced the IgGb and IgG3 antibodies above saline controls ( Fig. 2). The IgA antibodies, on the other hand, were Cobimetinib research buy enhanced in all groups after challenge ( Fig. 2). The predominance of the CA4 saponin,

although only modest after immunization, was more evident after infection. Indeed, compared to the respective antibody titers before infection, significant increases were detected in the CA4 saponin vaccinated mice after challenge for IgA (p = 0.0032), IgM (p = 0.0124), IgG (p = 0.0414), IgG2a (p = 0.0061) and IgG2b (p = 0.0349) antibodies while the CA3 saponin vaccine only showed an increase of the IgA (p = 0.0016) and Parvulin IgM antibodies (p = 0.0045). These results confirm the higher potency of the 4 sugar chain CA4 saponin ( Fig. 1) in the induction of anti-FML specific antibodies that was further enhanced after the infective challenge. The cellular immune response was initially evaluated by the intradermal reaction against Leishmania lysate (IDR) ( Fig. 3). IDR was measured in the right hind footpads and subtracted from the values of the left hind footpad injected

only with saline. At 24 h after immunization, the IDR response was significantly higher for the R saponin compared to all the other groups and also higher for the CA3 (mean = 0.06 mm) and CA4 (mean = 0.08 mm) than for the saline control (mean = 0.02 mm) ( Fig. 3A). At 48 h only the R and CA4 sustained this response indicating the superiority of CA4 over the CA3 saponin of C. alba. After challenge, only the R saponin vaccine sustained the enhanced IDR ( Fig. 3B). There was no significant variation, before and after infection, in the magnitude of the IDR response induced by the CA3 (p = 0.8103 at 24 h and p = 0.6818 at 48 h) or by the CA4 vaccines (p = 0.3898 at 24 h and p = 0.2801 at 48 h) ( Fig. 3A and B).