User talk:Mostafizur39

Diabetes & Heart disease relationship
'''People with diabetes also tend to develop heart disease or have strokes at an earlier age than other people. If you are middle-aged and have type 2 diabetes, some studies suggest that your chance of having a heart attack is as high as someone without diabetes who has already had one heart attack. Women who have not gone through menopause usually have less risk of heart disease than men of the same... age. But women of all ages with diabetes have an increased risk of heart disease because diabetes cancels out the protective effects of being a woman in her child-bearing years.

People with diabetes who have already had one heart attack run an even greater risk of having a second one. In addition, heart attacks in people with diabetes are more serious and more likely to result in death. High blood glucose levels over time can lead to increased deposits of fatty materials on the insides of the blood vessel walls. These deposits may affect blood flow, increasing the chance of clogging and hardening of blood vessels (atherosclerosis).'''

Mostafizur39 (talk) 14:06, 21 October 2011 (UTC)== We Learn Pharmacy ==

'''We Learn Pharmacy is a facebook page which is founded by Md.Mostafizur Rahman in 2010.

About this page by the founder:''' Pharmacy is a nobel subject.It is a very good professional subject also.But it is a matter of great sorrow that most of the people contain wrong idea on pharmacy.They consider it as the profession of selling medicaments.Besides to become established as a pharmacist,one will have to earn more and more knowledge on pharmacy.Our page has been designed to reach this targets.We will try to expense the knowledge of pharmacy through this page as way as possible.Hope all will help us to this mission. General Information This page is for all of the pharmacists and also pharmacy related professionals.

This page is administered by-

@Md.Mostafizur Rahman Bappi(creator) Student of 39th batch, Department of Pharmacy, Stamford University Bangladesh.

Mission : To earn knowledge of pharmacy as much as possible.  Link of page: http://www.facebook.com/#!/pages/We-Learn-Pharmacy/184951561518635

Importance of Ethics & Regulatory Affairs for assuring the Quality of the Pharmaceutical Products
'''Introduction: Drugs are very important substance in our life. Many new drugs are being discovered and developed day by day with the developing of diseases. To develop such drugs and medicines many other excipients are also used. If we want to get a better results or effects from the pharmaceutical products, we need to take care on the quality of the pharmaceutical products. Ethics and Regulatory Affairs are two important factors which help in assuring the quality of the pharmaceutical products. Pharmacists Code of Ethics plays a vital role in the Quality Assurance and Manufacturing of the pharmaceutical products. On the other hands, Regulatory Affairs also influences pharmacists to follow and maintain the various acts associated with the pharmaceutical manufacturing, sales, distribution, import, export and so on. Thus both Ethics and Regulatory Affairs equally contribute on assuring the quality of the pharmaceutical products. In this assignment we will see the basic concepts and role of both Ethics and Regulatory Affairs and also their importance for assuring the quality of the pharmaceutical products.

'''Ethics: “Ethics is a science, as being governed by principles of universal validity, so that, what was good for one was good for all and what was my neighbor’s duty was my duty also.” --- Socrates. Ethics means philosophy of moral behavior. Ethics is a system of moral principles that govern or influence a person’s behavior.”Code of Ethics” of a profession is nothing but all written or unwritten principles which are accepted in any profession as the basis of proper behavior constitute of ethics of the profession. Example: “Pharmacists Code of Ethics”-is a guideline to the pharmacist in their relationship with the patients, fellow practitioners, and other health care professionals and the public.

'''Pharmacy ethics: Pharmacy ethics is a branch of medical ethics that provides a framework for pharmacists to use in resolving questions about what ought to be done in pharmacy practice. To conduct an ethical exercise requires that one ask normative questions about what should be done, rather than that one ask only legal questions about what must be done, or empirical questions about why something is done. To address a question from an ethical perspective requires that one reflect on the morality of a situation; that one ask what will be the impact on others of one’s own action and whether one can justify one’s action to a higher authority.

'''Theories of Ethics: Modern medical ethics has its roots in two classical theories known as deontology and utilitarianism. It is a gross oversimplification to say that the deontological view is idealistic, while the utilitarian view is consequentialist, but that is an effective way of beginning to think of these two differing approaches to ethical theory. The deontologist is generally considered to be means and ends oriented, while the utilitarian is usually considered to be ends oriented only. In other words, for the deontologist the process matters more than the result, while for the utilitarian it is the result that matters most. Consider the hypothetical s situation of a clinical investigator who believes that a new drug to treat cancer will produce uncomfortable but temporary side effects. To persuade subjects to volunteer for clinical trials, the researcher is tempted to not disclose information about the side effects, reasoning that the overall good of proving the drug effective will benefit a large number of future patients, and will override the harm resulting from the side effects experienced by the small number of subjects in the clinical trial. This approach will likely be deemed invalid and inappropriate by both those who adhere to the idealistic, deontological view, and those who are adherents of the consequentialist, utilitarian view. But the criticisms these two theories offer of the plan will be different. Under the deontological view, one would likely argue that it is morally wrong ever to lie or to use a subject merely as a means to an end. The deontologist will be critical of the process that violates the principles of truth telling and respect for persons. On the other hand, the utilitarian would likely assert that if the deception is ever disclosed, future research would be impaired because prospective subjects would be distrustful of researchers and would not volunteer. The result of decreased participation in research would be unacceptable to the utilitarian. The withholding of information would do more harm than good. So, while the two theories might lead to the same conclusion about the unethical nature of the research, the theoretic al basis of the conclusion would differ significantly.

Principles of Ethics: Principle-based ethics has at times been criticized as too methodic and not sufficiently sensitive to the individual differences of ethical cases, but the study of pharmacy ethics would be incomplete without a description of the four basic ethical principles that apply in pharmacy ethics. The purpose of ethical principles is to determine the right of patients under the principles, and to then permit a decision about pharmacist duties that correlate with those rights. The primary objective of the principle -based approach is to enable a pharmacist to justify to himself or herself, and to others, the action taken in a given situation. The principle of autonomy (respect for persons) requires that individuals be permitted to make their own evaluations and choices when their own interests are at stake. If individuals are viewed as moral agents with their own unique approach to life (their own values, interests, attitudes and beliefs), then it would be disrespectful of individuals to reject their considered judgments or to deny them the liberty to act on those judgements. Autonomous individuals are at liberty to perform whatever actions they wish, as long as another autonomous individual’s actions are not infringed, even if the actions appear to be foolish or unwise based upon conventional and generally accepted wisdom. For example, under the principle of autonomy, a person who is a competent decision-maker is free to use a medication in a way that is less than optimally safe and effective, if the generally recognized “right way” to use the drug interferes with the person’s lifestyle. The principle of nonmaleficence (doing no harm) requires that pharmacists refrain from acting in ways that will cause harm or injury to others. A pharmacist who fails to counsel patients, for fear that the patients will discontinue using a drug if information about the drug is disclosed, is adhering to the principle of nonmaleficence, because it is through acts of commission that this principle is violated. Nonmaleficence prohibits both deliberate harmful action (substituting one generic drug product for another without authorization and without evidence of bioequivalence) and unintentional harm (inadvertently using the sig code for “take one tablet four times daily” for the label of a digoxin prescription that has directed the patient to take only one tablet daily. The principle of beneficence (doing well) requires positive action to (1) prevent what is bad, (2) remove bad or evil, and (3) do or promote good. It is through acts of omission that this principle is violated.  For example, the pharmacist described above who neglects to counsel patients is violating the principle of beneficence; because information about medications generally helps patients use their medications the correct way.  Health care providers, including pharmacists, have at times used the principle of beneficence as justification for doing for patients what, in t he care provider’s view, is best for the patient even if the patient prefers that it not be done. Beneficence of this type is sometimes referred to as “paternalism.” A paternalistic act toward a patient is an act that is done benevolently, either contrary to the patient’s expressed wishes, or without considering the patient’s wishes. The principle of justice (fairness) requires that all benefits and burdens be distributed equally. It requires that people be given that to which they are entitled. Distributive justice requires that resources be allocated in a fair way. Corrective justice requires that one who has harmed another place the harmed person back in a position the person would have been in had the harm not occurred (as well as this can be done with resources available). Justice is a principle that is difficult to apply in a practice setting, but it greatly facilitates the decisions made by policy makers.

Quality Assurance and Manufacturing of Pharmaceutical products according to Pharmacists Code of Ethics: I. Because of close integration between assurance and manufacturing both activities have been included in this section, there are however separate rules for pharmacists in quality control and manufacturing to be carried out independently but in cooperation. II. There should be comprehensive system so designed, documented and implemented and so furnished with personnel and equipment as to provide assurance that the products will be of quality appropriate to their intended use. The attainment of that quality objective requires the involvement and commitment of pharmacists responsible for both quality control and manufacturing. III. The objective of quality assurance is achieved when the process have been defined which when followed will yield a product which complies with its specification, and when the finished product- a.	contains the correct ingredients in correct preparation. b.	is of purity required. c.	has been correctly processed according to the defined procedure. d.	is enclosed in the proper container. e.	bears the correct labile, stored and distributed so that quality is maintained. IV. Quality control pharmacist should achieve effective control of quality by ensuring that: a.	Adequate facilities and staffs are available for inspection and testing of raw materials, finished products and intermediate bulk, and for the quality of the environment. b.	Samples raw materials, packaging materials and finished products and intermediate products. Personnel using methods approved under the direction of Quality Controller. c.	Result of inspection and testing of materials and intermediate bulk or d.	Sufficient reference samples of product are retained (where possible in final pack) to permit future examination if necessary. V. The pharmacists responsible for manufacturing should implement the basis requirements of good manufacturing practices by ensuring that: a)	The manufacturing process of designed before commencing of any activity. b)	Necessary facilities and resources are provided including •	appropriate trained personnel. •	adequate premises and space. •	suitable equipment. •	approved procedures. •	correct materials. •	suitable storage and transport. •	store of representation samples of each batch produced. c)	Procedures are written in instructional form in clear and unambiguous language. d)	Operators are trained to carry out procedures correctly. e)	Records are made during manufacturing including packaging to demonstrate that all steps required by the defined procedures were fact taken and the quality quantity produced were those expected. f)	Records of manufacture and distribution, which enable the history of a batch to be traced and retained in legible and acceptable form. g)	A system is available to recall any batch of product should that be necessary.

Regulatory Affairs: Regulatory affairs (RA), also called government affairs, are a profession within regulated industries, such as pharmaceuticals, medical devices, energy, and banking. Regulatory affairs also have a very specific meaning within the healthcare industries (pharmaceuticals, medical devices, biologics and functional foods). Regulatory affairs professionals (a regulatory professional) usually have responsibility for the following general areas: 	Ensuring that their companies comply with all of the regulations and laws pertaining to their business. 	Working with federal, state, and local regulatory agencies and personnel on specific issues affecting their business. i.e. working with such agencies as the Food and Drug Administration or European Medicines Agency (pharmaceuticals and medical devices); The Department of Energy; or the Securities and Exchange Commission (banking). 	Advising their companies on the regulatory aspects and climate that would affect proposed activities. i.e. describing the "regulatory climate" around issues such as the promotion of prescription drugs and Sarbanes-Oxley compliance. Pharmaceutical Regulatory Affairs: Pharmaceutical Regulatory Affairs professionals play an essential role in ensuring all pharmaceutical products comply with regulations governing the industry. Those working in pharmaceutical regulatory affairs jobs not only work in the initial application phase for a new or generic drug, but also in the licensing and marketing stages – making sure all operations and products meet required safety and efficacy standards. Professionals must combine knowledge of the business, legal and pharmaceutical industries to determine if regulations are being followed and in many cases form the link between pharmaceutical companies and regulatory authorities, such as FDA and EU. Regulatory affairs jobs in the UK and further fields are generally within the pharmaceutical, chemicals, biotechnology, medical devices and cosmetics industries. Organizations such as the FDA also provide roles for those interested working in the field.

Role of Regulatory Affairs Professionals: The primary responsibilities of pharmaceutical regulatory affairs professionals in clinical trials in order to get drug approval are mentioned below:- 	Literature Searching: Pharmaceutical Regulatory Affairs professional are responsible for searching literature regarding clinical trials as it enables to acquire an understanding of the clinical trial study and also keep us aware of relevant research that has already been conducted. 	Assembling Regulatory Submission: Pharmaceutical Regulatory Affairs professional is responsible for gathering information, preparing clinical trial dossiers and making regulatory submissions. Submissions include annual reports, addition of new investigators to clinical protocols, certificate of analysis, amendments proving for changes in clinical trials and routine and supplemental filings. 	Documentation: The most important part of pharmaceutical regulatory affair is that all the collected information should be documented. The reason is that conducting a clinical trial is a very lengthy process and requires a lot of time. So there might be a change of person working with the project. To tackle such situations documentation is essential. Pharmaceutical Regulatory service professional is responsible for keep an update on changes in regulatory guidelines. Being up to date in regulations is essential as it can affect the clinical trial process, regulation strategy and decisions on what kind of trials are needed etc. All changes in regulations must be documented and finally interpreted and communicated with the appropriate people in the company. 	Reporting of Serious Adverse Events: If any serious adverse event occurs during clinical trial, it is notified by sponsor to Pharmaceutical Regulatory service professional and they are responsible for reporting these adverse event reports in written form to the regulatory authorities. Thus they are the one who reports on the status of clinical trial. Apart from these, pharmaceutical regulatory affair professional facilitate in arranging the meeting of sponsor with drug regulatory authorities and also assist with the inspection and audits. They should also focus on the implementation of clinical studies with emphasis on study drug management and reviewing data from clinical trials. Importance of Regulatory Affairs for assuring the quality of Pharmaceutical Products: Regulatory affairs are also important in the pharmaceutical manufacturing area. As above discussion we have seen that Regulatory affairs are very important for ensuring all pharmaceutical products comply with regulations governing the industry. Besides Pharmaceutical Regulatory affairs also helps us to follow and maintain the various pharmacy law. Thus regulatory affairs play an important role in assuring the quality of pharmaceutical products following the various pharmaceutical law associated with pharmaceutical product manufacture and distribution. Now we will see some law related with Pharmaceutical products manufacturing, sale and distribution which largely contribute on assuring the quality of pharmaceutical products and must be followed through the regulatory affairs. There are many acts involved in drug manufacturing, sale and distribution. But the following 2 acts are largely followed in Bangladesh: 1)	The Drugs Act 1940 and 2)	The Drugs (Control) Ordinance, 1982.

 The Drugs Act 1940 for manufacture, sale and distribution of drugs: Many acts involved in the Drugs Act 1940. But the followings are the some important acts associated with manufacture, sale and distribution of drugs. These acts also influence on the quality of the pharmaceutical products. 	According to the section no.17, A drug shall be deemed to be misbranded- a)	If it is an imitation of, or substitute for, or resembles in a manner likely to deceive, another drug, or bears upon it or upon its label or container the name of another drug, unless it is plainly and conspicuously marked so as to reveal its true character and its lack of identity with such other drug; or b)	If it purports to be the product of a place or country of which it is not truly a product; or c)	If it is sold, or offered to exposed for sale, under a name which belongs another drug; or d)	If it is so coloured, coated or powdered or published that damage is concealed, or if it is made to appear of batter or greater therapeutic value than it really is; or e)	If it is not labeled in the prescribed manner; or f)	If its label or container or anything accompanying the drug bears any statement, design or device which makes any false claim for the drug or which is false or misleading in any particular; or g)	If the label or container bears the name of an individual or company purporting to be the manufacturer or producer of the drug which individual or company is fictitious or does not exist. For the purposes of section 18 a drug shall not be deemed to be misbranded or to be below standard quality only by reason of the fact that- a)	There has been added thereto some innocuous substance or ingredient because the same is required for the manufacture or preparation of the drug as an article of commerce in a state fit for carriage or consumption, and not to increase the bulk, weight or measure of the drug or to conceal its inferior quality or other defects; or In the process of manufacture, preparation or conveyance some extraneous substance has unavoidably become intermixed with it; provided that this clause shall not apply in relation to any sale or distribution of drug occurring after the vendor or distribution became aware of such intermixture. 	According to the section 22-(1) Subject to the provisions of section 23 and of any roles made by the Provincial Government in the behalf, an inspector may, within the local limits for which he is appointed, and in any other area with the permission of the of the licensing authority,- a)	Inspect any premises wherein any drug is being manufactured, the plant and process of manufacture, the means employed for standardizing and testing the drugs and all records and registers, related thereto; b)	Inspect any premises wherein any drug is being sold or stocked or exhibited for sale or in being distributed, the storage arrangement and all relevant records and registers; c)	Take samples of any drug which is being manufactured, or being sold or is stoked or exhibited for sale or being distributed; d)	Enter and search at all reasonable times with, such assistance, if any, as he considers necessary, and building, vessel or place, in which he has reason to believe, from personal knowledge or from information given by any person and taken down in writing, that an offence under this Act or any rules made there under, has been or is being committed; e)	Seize such drug and all materials used in the manufacture thereof and all over articles including registers, cash memos, invoices, bills which he has reason to believe may furnish evidence of the commission of an offence punishable under this Act and any rules made there under; f)	Call any person from the neighborhood to be present as witness in course of search, seizure or in connection with, any other matter where the presence of witnesses is necessary; g)	Require any person to appear before him at any proper place to give statement, assistance or information related to, or in connection with the investigation of an offence under this Act or rules made thereunder: Provided that the exemptions under sections 132 and 133 of the Code of Civil Procedure, 1908 (Act V of 1908), shall be applicable to requisitions for attendance under this clause; h)	Lock and seal any factory, laboratory, shop, building, storehouse, or godown or a part thereof where any drug is, or is being, manufactured, stored, sold, or exhibited for sale without the necessary license under this Act, or where he has reason to believe that an offence under this Act has been committed or may continue to be committed; i)	Forbid for a reasonable period not exceeding three months any person in charge of any premises from removing or disposing of any drug, article or other thing likely to be used in evidence of the commission of an offence under this Act or any rules made thereunder; j)	Exercise such other powers as may be necessary for carrying out the purposes of this Act or any rules made there under; According to the section 23, (2) Where the Inspector seizes any drug or any other article under section, 22, he shall tender a receipt therefore in the prescribed form. (3) Where an Inspector takes a sample of a drug for the purpose of test or analysis, he shall intimate such purpose in writing in the prescribed form to the person from whom he takes it and, in the presence of such person unless he willfully absents himself, shall divide the sample into four portions and effectively seal and suitably mark the same and permit such person to add his own seal and mark to all or any of the portions so sealed and marked: Provided that where the sample is taken from premises whereon the drug is being manufactured, it shall be necessary to divide sample into three portions only: Provided further that where the drug is made up in containers of small volume, instead of dividing a sample as aforesaid, the Inspector may, and if the drug be such that is likely to deteriorate or be otherwise damaged by exposure shall, take three or four, as the case may be, of the said containers after suitably marking the same and, where necessary, sealing them. 	According to section 33, (1) The provincial Government may, after consultation with the Board and after previous publication by notification in the official Gazette, make rules for the purpose of giving effect to the provisions of this chapter. (2) Without prejudice to the generality of the forgoing power, such rules may- a)	Provide for the establishment of laboratories for testing and analyzing drug ; b)	Prescribe the qualifications and duties of Government Analysts and the qualifications of the Inspectors; c)	Prescribe the methods of test or analysis to be employed in determining whether a drug is of standard quality; d)	Prescribe, in respect of biological and organo-metallic compounds, the units or methods of standardization; e)	Prescribe the forms of licenses for the manufacture for sale, for the sale and for the distribution of drugs or any specified drug or class of drugs, the form of application for such licenses, the conditions subject to which such licenses may be issued, the authority empowered to issue the same and the fees payable therefore; f)	Specify the diseases or ailments which a drug may not purport or claim to cure or mitigate and such other effects which a drug may not purport or claim to have; g)	Prescribe the conditions subject to which small quantities of drugs may be manufactured for the purpose of examination, test or analysis; h)	Require the date of manufacture and the date of expiry of potency to be clearly and truly stated on the label or container of any specified drug or class of drugs, and prohibit the sale, stocking or exhibition for sale, or distribution of the said drug or class of drugs after a expiry of the date of potency; i)	Prescribe the conditions to be observed in the packing in bottles, packages and other containers of drugs, and prohibit the sale, stocking or exhibition for sale, or distribution of drugs packed in contravention of such conditions; j)	Regulate the mode of labeling packed drugs, and prescribe the matters which shall or shall not be included in such labels; k)	Prescribe the maximum proportion of any poisonous substance which may be added to or contained in any drug, prohibit the manufacture, sale or stocking or exhibition for sale, or distribution of any drug in which that proportion is exceeded, and specify substances which shall be deemed to be poisonous for the purposes of this Chapter and the rules made there under; l)	Require that the accepted scientific name of any specified drug shall be displayed in the prescribed manner on the label or wrapper of any patent or proprietary medicine containing such drug; m)	Prescribe the form of warranty referred to in subsection (1) of section 19; n)	Regulate the powers and duties of Inspectors; o)	Prescribe the forms of report to be given by government analyst, and the manner of application for test or analysis under section 26 and the fees payable therefore; p)	Specify the offences against this chapter or any role made there under in relation to which the stock of drug shall be liable to confiscation under section 31; q)	Provide for exemption, conditionally or otherwise, from all or any of the provisions of this Chapter of the rules made there under, of any specified drug or class of drugs.  The Drugs (Control) Ordinance, 1982. Many acts involved in The Drugs (Control) Ordinance, 1982. But the followings are the some important acts associated with manufacture, sale and distribution of drugs. These acts also influence on the quality of the pharmaceutical products.

Registration of medicines.— (1)	No medicine of any kind shall be manufactured for sale or be imported, distributed or sold unless it is registered with the licensing authority. (2)	The licensing authority shall not register a medicine unless such registration is recommended by the committee. (3)	A registration shall be granted on such conditions as may be specified by the licensing authority. (4)	A registration shall, unless cancelled earlier, be valid for a period of five years.

Cancellation or suspension of registration.— (1)	The licensing authority may cancel the registration of any medicine if such cancellation is recommended by the Committee. (2)	The Committee shall evaluate every medicine registered before the commencement of this Ordinance and every medicine that may be manufactured or imported after such commencement in order to determine its safety, efficacy and usefulness. (3)	If on such evaluation the Committee finds that any such medicine is not safe, efficacious or useful it may recommended to the licensing authority cancellation of registration of the medicine. (4)	The licensing authority may, if it is satisfied that a medicine is substandard, suspend the registration of such medicine till he is satisfied that the medicine has attained its standard. Fees for registration. — No registration of medicine shall be granted unless a fee to be determined b the Government is paid at the time of application for registration. Prohibition of Manufacture, etc. of certain medicines.— 1)	On the commencement of this Ordinance, the registration or license in respect of all medicines mentioned in the Schedules shall stand cancelled, and no such medicine shall, subject to the provisions of sub-section (2), be manufactured, imported, distributed or sold after such commencement. 2)	Notwithstanding anything contained in sub-section (1).— a.	the medicines specified in Schedule I shall be destroyed within three months from the date of commencement of this Ordinance; b.	the medicines specified in Schedule II may be manufactured or sold for a period of six months from the date of commencement of this Ordinance and thereafter their manufacture and sale shall be permitted only if they are registered after change in their formulation in accordance with the direction of the licensing authority; c.	The medicines specified in Schedule III may be manufactured, imported, distributed and sold for a period of nine months after the commencement of this Ordinance, and thereafter there shall not be any manufacture, import, distribution or sale of such medicines. Restriction on import of certain pharmaceutical raw material.— 1)	No pharmaceutical raw material necessary for the manufacture of any medicine specified in any of the Schedules shall be imported. 2)	No drug or pharmaceutical raw material shall be imported except with the prior approval of licensing authority. 3)	The licensing authority may award an approval under sub-section (2) on such conditions as it deems fit to specify. Restriction on manufacture of certain drugs under license. — No drug shall, after six months from the date of commencement of this Ordinance, be manufactured in Bangladesh under license granted by a foreign company having no manufacturing plant in Bangladesh if, such drug or its substitute is produce in Bangladesh. Fixation of price of drugs.— 1)	The Government may, by notification in the official Gazette, fix the maximum price at which any, medicine may be sold. 2)	The Government may by notification in the Official Gazette, fix the maximum price at which any pharmaceutical raw material may be imported or sold. Conclusion: From the above discussion we can say that ethics and regulatory affairs largely influence on the manufacture, therefore the quality of the pharmaceutical products. So it is said that Ethics and Regulatory Affairs are equally important for assuring the quality of the pharmaceutical products.

Reference Websites

i.	http://en.wikipedia.org/wiki/Regulatory_affairs ii. http://allianceinstitute.org/drug_development_regulatory_affairs.php iii. http://www.pharma-iq.com/regulatory-legal/articles/career-spotlight-pharma-regulatory-affairs iv. http://pharmacy.auburn.edu/pcs/onlinedemo/jurisprudence/pdf/lesson01.pdf