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It can be assumed that future enemies probably will create such a state in American prisoners of war discount ranitidine 150mg otc gastritis gagging, although they may not do so with any sophisticated intent cheap ranitidine 150 mg on-line gastritis diet . Historically generic 150mg ranitidine free shipping gastritis vomiting blood, it has been the common practice of captors, police, and inquisitors to isolate their prisoners in places that are cold, damp, hot, unventilated, unsanitary, and uncomfortable, to deprive them of food, fluids, sleep, and rest and medical care, and to beat, torture, harry, overwork and threaten them, as well as to question them interminably with leading questions. Such procedures have been used partly because they make prisoners more "pliable," more "ready to talk," and more "cooperative. Some Circumstances under Which Brain Function May Be Disturbed without Demonstrable Disturbance of Other Bodily Functions The phenomena just considered relate to men who have suffered some disturbance of their homeostasis — some measurable change in the internal environment affecting the body as a whole, other organs as well as the brain. People who experience the effects of isolation, fatigue, or sleep loss may show no measurable disturbance of their general homeostasis. They may nonetheless exhibit impaired brain function, for the brain has special vulnerabilities over and above those that it shares with other organs. It is possible to have disturbed brain function in the absence of any other significant alteration in homeostasis. The accumulation and transmission of information in this sense is a characteristic of all living organisms. The nervous system of the higher animals is a specialized apparatus capable of dealing with information in complex ways and thereby greatly increasing the general adaptive capacities of the animal. It takes in information from the organs of special sense, and from the sensory nerve endings within the body and its surfaces, and transmits this information to the brain. There it is analyzed, organized, evaluated, stored, and used as a basis for organizing the activities of the man as a whole. We might say that "information" arising from the configurations of minute amounts of energy is the substrate for the activities of the brain, in somewhat the same sense that "food" is the substrate for the activities of the gastrointestinal tract. Nor can the brain perform one sort of activity continuously and maintain its efficiency. Even though the task undertaken is entirely "mental" (or, as one might say, involves only the carrying out of activity within the brain), and no significant changes in the general physical state of the individual occur as a result of it, the phenomenon of "fatigue" eventually supervenes, and brain function deteriorates (4, 32, 41). In addition to this, the brain requires "sleep" from time to time — a cessation of its "conscious" pattern of activities; otherwise its functions suffer (35, 64, 84, 98, 118). Thus the brain has special vulnerabilities of its own; it cannot function "normally" unless it receives a certain amount of information upon which to operate, and it cannot carry out a single pattern of activities unremittingly and indefinitely. Isolation The experiments of Hebb and others (11, 44, 45, 53, 55, 56, 80, 109, 126), who have concerned themselves with "sensory deprivation," have consisted of putting men into situations where they received no patterned input from their eyes and ears, and as little patterned input as possible from their skin receptors. In some cases there was a -28- diminution in sensory input itself; but it appears to have been the lack of patterning, the paucity of information, that was important. Their capacity to carry out complex tasks and to perform well on psychological tests fell away. They developed illusions, delusions, and hallucinations, a mood of fearfulness, and many of them discontinued the experiment. Such experimentally contrived situations are by no means the same as those of persons in prolonged prison isolation, yet undoubtedly some aspects of these observations on sensory deprivation are applicable to our understanding of the reaction of the individual to prolonged isolation. It is well known that prisoners, especially if they have not been isolated before, may develop a syndrome similar in most of its features to the "brain syndrome" (57, 58, 91). In due time they become disoriented and confused; their memories become defective and they experience hallucinations and delusions. In these circumstances their capacity for judgment and discrimination is much impaired, and they readily succumb to their need for talk and companionship; but their ability to impart accurate information may be as much impaired as their capacity to resist an interrogator. Classically, isolation has been used as a means of "making a man talk," simply because it is so often associated with a deterioration of thinking and behavior and is accompanied by an intense need for companionship and for talk. The prisoner himself may be taken in by this and later stoutly maintain that the interrogator "never laid a hand on me. The fact that some people, who have been through prison isolation before, or who can create for themselves an active and purposeful inner life of fantasy, can endure isolation for a long time (5, 15, 75) does not vitiate the fact that total isolation effectively disorganizes -29- many people who are initially obliged to undergo it, even when it is not carried out under circumstances of uncertainty and threat, as it usually is. There appears to be a wider range of variability in the capacity of men to withstand isolation, sleep deprivation, and fatigue than in their ability to withstand dehydration or fever, for example, even though ultimately brain function may be deranged by all these conditions. Sleep Deprivation For reasons not yet known, a brain cannot continue to function without occasional periods of sleep. Some can function effectively for fairly long periods with relatively few hours of sleep obtained at irregular intervals (64, 68). Under experimental conditions men have been known to endure for more than a hundred hours without sleep at all (16, 35, 46, 72, 98, 118, 123), and for more than two hundred hours with only a few brief naps (64). Yet most people deteriorate markedly after about seventy-two hours without sleep, and all deteriorate sooner or later (35, 46, 64, 118, 122). The highest functions suffer first; the capacity to cope with complex and changing situations without making mistakes or errors in judgment is often the first to go. This is followed by a deterioration of dress, speech, and behavior; dullness; emotional lability; defects of recent memory; disorientation; hallucinations, delusions, thinking disturbances; and impaired judgment and intellectual functions, all increasing in severity with the passage of time (35, 46, 64, 72, 98, 118, 122). Even at a fairly late stage of this deterioration, people faced with an acute challenge and highly motivated to meet it may briefly perform complex tasks quite adequately; but ultimately even this capacity is lost (4). Sleep deprivation affects brain function directly, while producing little or no change in the general internal milieu. Efforts to demonstrate a disturbance of the general homeostasis consistently associated with lack of sleep have been largely futile (84, 118). The constituents of the blood and the function of organs other than the brain may show little or no abnormality in those who have been without sleep for many hours. People whose thinking and behavior are seriously deranged may show "nothing wrong with them" on physical examination or various chemical tests. We shall use it to denote a group of somewhat similar phenomena which occur in muscles, in reflex arcs, and in the brain. It is associated with measurable changes within the muscular system, and it has its counterpart in the “muscle fatigue” that occurs in the intact man after muscular activity. On the other hand, “fatigue” of the man as a whole has been given various definitions (4, 32, 88). It is often seen in people who are depleted or ill, but no measurable bodily change is necessary to it or consistently associated with it. The “fatigue syndrome” may be produced in a man if he is put to performing a given task over and over, without rest and without change. After a while he performs this task less rapidly, less efficiently, less effectively, and with more mistakes. This falling off in his performance on the specific task is usually accompanied by a feeling of “weariness,” or “fatigue. In addition, the rapidity with which the fatigue syndrome develops is influenced by the attitude of the man to the task that he must perform (4, 32, 81). However, the most extreme degrees of fatigue that have been studied have been associated with combat or with other extremely trying military operations where muscular activity, lack of sleep, and sometimes injury played a part in their production (4, 8, 13, 32, 41, 49, 50, 81, 83, 88, 111, 114, 115, 135). The fatigue that occurs in combat or other military operations is like that occurring during the prolonged and unremitting interrogation carried out by state police in various countries (57).

Onset of Action Duration Hyperprolactinemia 2 h 24 h Parkinson’s disease 30–90 min No data Acromegaly 1–2 h 4–8 h Food: Take with food or milk order ranitidine cheap diet by gastritis. Contraindications: Severe ischemic heart disease order genuine ranitidine on-line chronic gastritis low stomach acid, peripheral vas- cular disease buy 300mg ranitidine overnight delivery gastritis y colitis, sensitivity to ergot alkaloids. Warnings/precautions: Use with caution in patients with kidney disease, liver disease. Advice to patients • Avoid driving and other activities requiring mental alertness or that are potentially dangerous until response to drug is known. Clinically important drug interactions • Drugs that increase effects/toxicity of bromocriptine: sympa- thomimetics, diuretics. Editorial comments: Alarge percentage of patients will experience mild to moderate side effects from bromocriptine, particularly with higher doses (>20 mg/d). In postpartum studies, only 3% of patients needed to discontinue therapy because of side effects. Although brompheniramine is considered compatible with breastfeeding by the American Academy of Pediatrics, it is stated to be contraindicated by one manufacturer. Warnings/precautions • Use with extreme caution in patients with active peptic ulcer, severe coronary artery disease, symptomatic prostatic hypertro- phy. Advice to patient • Avoid driving and other activities requiring mental alertness or that are potentially dangerous until response to drug is known. Editorial comments: This drug is available in combination with other agents, including pseudoephedrine, phenylephrine, phenyl- propanolamine, aspirin, acetaminophen. Warnings and precautions, side effects, etc, of other ingredients should be kept in mind when prescribing. Mechanism of action: Inhibits elaboration of many of the media- tors of allergic inflammation, eg, leukotrienes and other products of the arachidonic acid cascade. Maintenance: reduce initial dose to smallest amount necessary to control symptoms. Warnings/precautions • If patient is transferred from systemic corticosteroid to inhala- tion drug, symptoms of steroid withdrawal may result. Alternatively, adre- neal insufficiency may occur: weakness, fatigue, nausea, anorexia. This may minimize the development of dry mouth, hoarseness, and oral fungal infection. Parameters to monitor • Signs and symptoms of acute adrenal insufficiency, particu- larly in response to stress. If these occur, the dose of systemic steroid should be increased followed by slower withdrawal. Editorial comments • Inhaled corticosteroids are the drugs of choice for patients with refractory symptoms on prn adrenergic agonist bron- chodilators. However, there is considerable controversy with respect to the beneficial use of higher than recommended inhalation doses of these drugs. Mechanism of action: Inhibits sodium and chloride resorption in proximal part of ascending loop of Henle. Contraindications: Hypersensitivity to sulfonamides, anuria, hepa- tic coma, severe electrolyte depletion. Editorial comments • This drug is listed without detail in the Physician’s Desk Reference, 54th edition, 2000. Class of drug: Local and regional anesthetic Mechanism of action: Reversibly inhibits initiation and conduc- tion of nerve impulses near site of injection. Contraindications: Hypersensitivity for amide-type local anes- thetic (eg, lidocaine), sensitivity to sodium metabisulfate (in prepa- rations containing epinephrine), obstetrical paracervical block. Warnings/precautions • Use local anethetics plus vasoconstrictor (eg, epinephrine, nor- epinephrine) with caution in patients with the following con- ditions: peripheral vascular disease, hypertension, administration of general anesthetics. Use with extreme cau- tion for lumbar and caudal epidural anesthesia in patients with the following conditions: spinal deformities, existing neurologic dis- ease, severe uncontrolled hypotention, septicemia. Any increase in heart rate and sys- tolic pressure within 45 seconds (the epinephrine response) would indicate that the injection is intravascular. The necessary means must be avail- able to manage this condition (dantrolene, oxygen, supportive measures). Advice to patient: Be aware that there will be a loss of sensation for several hours after the injection. At the first sign of a change that suggests onset of toxicity, administer oxygen and stop drug. Establish and maintain a patent airway, begin assisted ventilation, and administer 100% oxygen. Resuscitation equipment and drugs, as well as oxygen, should be available for immediate use. Mechanism of action: Binds to opiate receptors and blocks ascending pain pathways. Adjustment of dosage • Kidney disease: creatinine clearance <30 mL/min: 50–100 mg q12h Maximum: 200 mg. Warnings/precautions • Use with caution in patients with the following conditions: head injury with increased intracranial pressure, serious alco- holism, prostatic hypertrophy, chronic pulmonary disease, severe liver or kidney disease, postoperative patients with pulmonary dis- ease, disorders of biliary tract. If nausea and vomit- ing persist, it may be necessary to administer an antiemetic, eg, droperidol or prochlorperazine. This drug can cause severe hypotension in a patient who is volume depleted or if given along with a phenothiazine or general anesthesia. Editorial comments • Naloxone may not be effective in reversing respiratory depres- sion from buprenorphine. American Academy of Pediatrics expresses concern regarding antidepres- sants and breastfeeding. Advice to patient • Avoid driving and other activities requiring mental alert- ness or that are potentially dangerous until response to drug is known. Adverse reactions • Common: dizziness, headache, insomnia, dry mouth, nausea/ vomiting, diaphoresis, constipation, tremor, agitation, weight change, sedation. Parameters to monitor • Suicidal tendencies until there is improvement of depression. Editorial comments • High doses of bupropion (up to 450 mg/d) increase seizure potential 4 times greater than other antidepressants. American Academy of Pediatrics expresses concern regarding antianxiety drugs and breastfeeding. Warnings/precautions • Use with caution in patients with the following conditions: kidney disease (see above), liver disease (see above). Advice to patient • Avoid driving and other activities requiring mental alertness or that are potentially dangerous until response to drug is known. Editorial comments: This drug has not been proven to be effec- tive for long-term use. Warnings/precautions • Use with caution in patients with the following conditions: previous radiation treatment, recently administered immuno- suppressive drugs and other agents that are toxic to bone marrow. This treatment has also been associated with menopausal symptoms, hepatic veno-occlusive disease, and possibly cardiac tamponade.

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Schematic diagram of pharmacophore proposed by Chang et al (J Med Chem 47 (2004) 6529) discount ranitidine 150mg amex chronic gastritis/lymphoid hyperplasia. At the center is the aromatic core which is surrounded by three lipophilic regions purchase ranitidine 300mg free shipping gastritis diet , Lip1 discount ranitidine 150mg visa gastritis diet , Lip2, and Lip3. Below the aromatic core are the hydrogen bond acceptor and donor region, Acc1 and Don1, respectively. On the right of the aromatic core, a second hydrogen bond acceptor, Acc2, is located. General procedure for the preparation of compounds 3a-3k under microwave conditions. The reaction mixture was stirred and heated at 165 °C under microwave conditions for 30 min. As reviewed in chapter 2, substructure-based methods are valuable research tools in cheminformatics and medicinal chemistry research. As already discussed in chapter 2, the analysis of the structural parts that constitute molecules, such as rings and ring systems, is biased towards chemists. In contrast, exhaustive substructure-based methods consider all possible substructures that occur in the molecules, and do not suffer from this bias. This type of large-scale screening of molecular libraries would be virtually impossible without the recent advances in frequent substructure mining algorithms. The algorithm used throughout the first three research chapters, named Gaston, proved very versatile. For instance, the substructures found in the screening library used in Chapter 3, predominantly esters and carboxamide moieties, reflected the synthetic reactions used to construct the library. Hierarchically narrowing down the sets from superfamily, to receptor family, to receptor, and to receptor subtype, revealed well-known motifs as well as new substructural features. These included the imidazole-like substructure common in histamine receptor ligands and the planar ring system consisting of a fused five- and six-membered ring (indole-like substucture) often present in serotonin receptor ligands. As expected, the use of different chemical representations had the effect of finding different sets of characteristic structural features in a library. Varying the chemical representation of a library can be explored further, however, there will always be a trade-off between specificity and diversity. For instance, the normal chemical structure drawing representation was most specific in identifying compounds of a set but performs worse on libraries that are more dissimilar. The work of chapter 3 showed that frequent substructure mining is capable of identifying both well-known and new structural motifs that are characteristic for phylogenetic subsets (e. This tree expresses the structural overlap between ligands of different receptors and therefore which receptors are more likely to share a common ligand. Thus, the tree provides insight into possible side-effects and can be used as a ‘deorphanization’ tool to find new ligands for a receptor by starting with ligands from ‘nearby’ receptors. In this particular case we screened a commercial vendor library for new ligands for the A2A adenosine receptor. New ligands were found and prioritized that were truly different from existing A2A adenosine receptor ligands. This analysis was quite successful, as we learned that many compounds recognized the adenosine receptors when tested in an experimental setting. For reasons of cost-effectiveness we included one vendor only; it is to be expected that the possible inclusion of more libraries would increase the diversity of ligands even further. In chapter 6, our screening concept was extended from screening existing compounds to exploring chemical space. For this we used a derivative of our Molecule Evoluator software, called the Molecule Commander. This prototype was used as a first component in a typical drug design workflow (PipelinePilot®) that combined requirements such as affinity for the desired target (the adenosine A1 receptor in this case) with constraints such as Lipinski’s Rule of Five. This offers the perspective of a chemist formulating a research question and/or drawing one or more molecules, after which the computer is instructed to search compound databases, optimize molecules, and present a range of best possible ideas to the chemist. In particular the use of more abstract substructures as described in Chapter 3 brought significant advantages. In retrospect we have the impression that the vocabulary of the medicinal chemist is largely based on compound features important for chemical reactivity. The explicit use of ‘rings’, ‘bonds’ and ‘functional groups’ as substructures may largely stem from a medicinal chemist’s background in synthetic organic chemistry. For the desired biological effect it would be helpful – and Chapter 3 is proof of that – to focus on the pharmacologically relevant substructures. In the current set-up substructures can be anywhere in the molecule, and lack information about the precise location, e. This also has an impact on the connectivity of an atom, which is essentially lost in this approach. The representation of bonds can also be problematic from the way molecules are represented in databases. For instance, the representation of an aromatic ring system can be quite different in databases, and this may have consequences for the perceived substructure. Likewise, keto/enol tautomerism can cause ambiguity in the process of defining substructures. When the substructures are eventually used for virtual screening purposes – as in Chapter 5 – another question arises: if one substructure is good, would two of the same be better? That is not necessarily the case for a biologically active molecule, but without further precautions a simple summation of fragments may lead to erroneous conclusions, as e. In the world of bioinformatics there has always been the notion that databases holding e. Many compound databases were either prohibitively expensive for academic use or simply not accessible (e. It is a database of drug-like small molecules, with bioactivities abstracted and curated from available scientific literature and patents. As with all databases care should be taken as errors tend to propagate; we noticed several errors ourselves, such as wrong bioactivity data, wrong structures, all probably inevitable in such huge data compilations. In fact, this is the consequence of the transformation from information in published documents such as scientific papers towards data storage. This involves the human mind and possible interpretation errors, the conversion of flat text into structured data such as in databases, and potentially many more ‘conversion’ errors. A better approach would be to remove these intermediate steps of flat text publishing and data extraction and instead make the data directly available in structured format. However, when data is entered in standard databases, most of the context that would normally be provided in an article is lost. Some data providers attempt to offer some context as extra fields in database tables. However, this is done fairly ad-hoc and not in a standardized manner, and these additions therefore lack any real meaning. These shortcomings are increasingly realized nowadays, but aligning and integrating proprietary and public 221 Chapter 7 data sources into a single system is a difficult and time consuming task.

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The point of intersection of these lines ultimately gives rise to the desired end-point cheap ranitidine 300 mg with mastercard gastritis diet 50\/50. A good number of amperometric titrations may be performed on considerably dilute solutions (say buy cheap ranitidine on line gastritis diet , 10–4 M) at which neither potentiometric nor visual indicator methods ever can give precise and accurate results cheapest ranitidine gastritis diet eggs, and 4. In order to eliminate the migration current (Im) completely either the ‘foreign salts’ already present cause little interference or invariably added so as to serve as the ‘supporting electrolyte’. It is duly controlled and monitored by the potential divider (R) and is conveniently measured with the help of a digital voltmeter (V). Finally, the current flowing through the circuit may be read out on the micro-ammeter (M) installed. The following steps may be carried out in a sequential manner for an amperometric titration, namely : 1. A known volume of the solution under investigation is introduced in the titration cell, 2. The apparatus is assembled and electrical connections are duly completed with dropping mercury electrode (C) as cathode and saturated calomel half-cell as anode, 3. A slow stream of pure analytical grade N2 – gas is bubbled through the solution for 15 minutes to get rid of dissolved O2 completely, 4. Applied voltage is adjusted to the desired value, and the initial diffusion current (Id) is noted carefully, 5. A known volume of the reagent is introduced from the semimicro burette (B), while N2 is again bubbled through the solution for about 2 minutes to ensure thorough mixing as well as complete elimination of traces of O2 from the added liquid, 6. The flow of N2 gas through the solution is stopped, but is continued to be passed over the surface of the solution gently so as to maintain an O2 free inert atmosphere in the reaction vessel, 7. Finally, the said procedure is repeated until sufficient readings have been obtained to allow the equivalence point to be determined as the intersection of the two linear portions of the graph thus achieved. There are holes (H) in the stem of the mercury reservoir for making electrical contact with it. The mercury reservoir is provided with a flange fitted inward to prevent Hg from being thrown out. The electrical connection is duly done to the electrode by means of a strong amalgamated Cu-wire passing through the glass tubing to the lower end of the Hg covering the sealed-in platinum wire ; the upper end of which passes through a small hole made in the stem of the stirrer and dips well into the Hg present in the Hg seal. Subsequently, a wire from the Hg seal is connected to the source of applied voltage. The glass tubing serves as the stem of the electrode that is rotated at a constant speed of 600 rpm. Glass-tubing 6-7 mm Copper wire G 21-22 mm 5 cm Mercury H C reservoir H Copper wire E 21 cm Mercury B F – + A Platinum wire Length = 5. E = Salt bridge, F = Potential divider, G = Galvanometer, H = Sensitivity shunt, and I = Calomel cell. Evidently, this particular technique is a modification of the classical amperometric titration. This technique is specifically applicable to only such systems where the phenomenon of oxidation-reduction exists both before as well as after the equivalence point has been duly accomplished. It essentially makes use of two identical, stationary microelectrodes immersed in a well stirred solu- tion of the sample. A small potential ranging between these electrodes ; and the resulting current is measured subsequently as a function of the volume of reagent added. The end-point is distinctly characterized by a sudden current rise from zero or a decrease in the current to zero or a minimum at zero in a V-shaped curve. Though this technique was first used in 1926, but it received its due recognition only around 1950**. The various components are as follows : A, A = Twin-polarized Platinum microelectrodes, B = Micro-ammeter (µA), C = 500 Ω, 0. The potentiometer is adjusted in such a fashion that there is a distinct potential drop of about 80 to 100 millivolts between the two platinum electrodes. Add to it 25 ml of the buffered supporting electrolyte, and 5 ml of the gelatin solution, 4. Determine the end-point and calculate the number of milligrams of Pb in the given sample, and 8. It is essential to bubble N2 through the solution for 10–15 minutes before the titration and while addition of reagents are made. Again, correct the currents for dilution, plot the graph, determine the end-point, and report the number of milligrams of Pb present in the given sample. Discuss the four typical amperometric titration curves obtained in amperometric method of analysis and exam- ine them critically with appropriate examples. Attempt the following with regard to ‘amperometry’ : (a) Corrections for the volume change, and (b) Advantages. How would you assay the following medicinal compounds amperometrically : (i) Procaine hydrochloride, (ii) Procainamide hydrochloride, (iii) Presence of Ni with dimethylglyoxime, and (iv) Presence of Pb with K2Cr2O7 solution. Heineman,Laboratory Techniques in Electroanalytical Chemistry, New York, Marcel Dekker, 1984. It has been observed that when a ray of light happens to pass from one medium (a) into another medium (b) it is subjected to refraction (Figure 18. In other words, the ray travels at a lower velocity in the relatively more optically dense medium (b) than in medium (a) which is less optically dense. It is a common practice to compare the refractive indices of liquids to that of air. Considering a narrow band of rays, x-y, held near to the boundary between the two media ‘a’ and ‘b’ (Figure 18. This particular band has a sharp edge at y, where the actual ray (y-y) may be seen. It is pertinent to mention here that the refractive index of a substance is not a static (constant) property of the substance but it alters with (a) wavelength and (b) temperature. Therefore, conventionally the temperature at which the refractive index is measured is usually desig- nated as a superscript numerical on n ; whereas the wave-length of light employed as a subscript capital. Molar Refractivity : Later on, a still more useful property termed as the molar refraction (or refrac- tivity) was introduced which could be expressed as follows : 2 F n − 1I M R = G 2 J... Interestingly, both specific refraction [n] and molar refraction (R), being temperature independent, should have the same values for a given substance either in the solid, liquid or gaseous state, provided the molecular structure is unchanged. Unit of Molar Refraction : As the refractive index is a dimensionless quantity, the units of molar refraction are simply those of molar volume, M/p i. Atomic Refractivities : Atomic refractivities may be attributed by virtue of : (a) Structural features e. A few representative atomic refractivities and bond contributions are given in Table 18. The upper face of the lower prism has a ground surface so as to diffuse the light rays in every possible direction. The rays passing from the liquid to the upper prism undergoes refraction in the normal manner, thereby providing a bright field in the eye-piece. The critical ray is originated by virtue of the rays that strike the liquid glass interface at the grazing incidence. As an outcome of these combined effects the ‘field of view’ is represented as a distinct dark and light area having a sharp dividing line.

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