Microsoft word - letter to mail online 030912

Dear Mr Wheeler,
I am writing to you with regards to the article published in the Mail Online on 3rd
September 2012, entitled “Electronic cigarettes ‘could damage your lungs’ as they
cause less oxygen to be absorbed by the blood.”i We feel that, in the interests of your
readership, it is important to point out a few relevant facts, so that future reporting
may be more accurate.
The ‘latest research’ to which you refer is an, as yet, unpublished study from the
University of Athens in Greece, which has not been peer-reviewed. The abstract of the
study was presented at the European Respiratory Society’s Annual Congress in
Vienna, and Professor Christina Gratziou, one of the authors, spoke at a press
conference, which appears to be the origins of this ‘story’.
Electronic cigarettes are not “touted as a safe alternative to smoking”, suggesting
that this is somehow nefarious or misleading; they most definitely are orders of
magnitude safer than smoking – a conclusion borne out by Professor Gratziou’s
abstract. Therefore, it is entirely appropriate for providers of these products to inform
their customers of this fact.
It is highly irresponsible journalism to publicly slur a harm reduction product which is
already saving millions of lives. These could save many millions more if smokers were
told the truth about their options, instead of publications like yours continuing to
perpetuate the lies put about by those with competing interests. It is a very sad truth
that it takes so few words of misinformation to cause significant damage, and so
many to uncover the facts.
Unfortunately, the article (and indeed, Professor Gratziou) is inaccurate in suggesting
that the available data proves that the use of electronic cigarettes causes damage to
the lungs. The abstract does not, in fact, support the claim that any damage is
caused, merely that there is an observable effect. You state that the reported rise in
airway resistance means that “less oxygen is absorbed by the blood”. There is not a
shred of evidence to support this, nor is it even mentioned in the study abstractii, or
press release.
It appears to be a complete invention of the Mail Online, and it has since been
regurgitated elsewhere. Not only was blood saturation not measured or mentioned in
either Professor Gratziou’s study abstract or her subsequent press release, but there
is no reason to suppose that a slight increase in airway resistance would lead to a
reduction in oxygen in the blood. Our assessment is supported by Professor Michael
Siegel, who said:
“Even more fallacious is the claim that the study found that electronic cigarettes
cause hypoxemia (lowered oxygen in the blood). . a small increase in airway
resistance is not going to cause hypoxemia”iii
You report that the researchers found that “[o]n average the effect lasted for ten
minutes”. Presumably, this is what Professor Gratziou (quoted later in your article) is
referring to as “immediate harm”. The fallacy of this can be easily demonstrated by
the fact that the effect on respiratory function was transitory, lasting for only 10
minutes, particularly when compared with the proven long-term harm caused by
inhaling tobacco smoke. Furthermore, this would certainly not suggest long-term
harm, especially when considered in the context of widely-available, published, and
peer-reviewed studies.
All electronic cigarette products are required, by existing consumer product safety
legislation, to undergo stringent quality and safety testing. Your assertation that
electronic cigarettes “don’t have to undergo checks” exemplifies the increasing
tendency for opponents of the electronic cigarette to ‘bandy about’ the terms
“unapproved” and “unregulated”. This is a method used to artificially heighten the
perceived risk, since what is actually meant is “unapproved” and/or “unregulated” as
a medicine. In this context, coffee is an “unapproved” and “unregulated” caffeine
delivery product. This does not make it dangerous, despite the known cardiovascular
risks of caffeine use. This is inflammatory language, designed to scaremonger - much
like your repeated use of the word ‘damage’ (not to mention the seemingly obligatory
mention of ‘cancer’). Even the Professor doesn’t mention ‘damage’, but (albeit
inaccurately) talks about ‘harm’, despite the fact that this bears little resemblance to
the study’s findings as published in the abstractiv.
It is also very misleading to imply that they are ‘unsafe’ “before being put on sale in
high street chemists.” This makes it seem that electronic cigarettes are some kind of
dodgy medicinal product, sneaking onto the pharmacy shelves while no-one is
looking! In fact, they are required to be rigorously tested, and are on sale in all sorts
of different outlets, including supermarkets, petrol stations, corner shops, Harrods
and Selfridges, as well as being widely available online – and yes, in some chemists,
too.
The sale of these ‘unapproved’ and ‘unregulated’ products is covered by the following regulations, and enforced by Trading Standards, the National Measurement Office, VCA, the Environment Agency, Public Analysts, HM Revenue and Customs, and the MHRA (only if medical claims are made): • General Product Safety Regulations 2005, as amended by CHIP4, CLP and • Chemicals (Hazard Information and Packaging for Supply) Regulations (CHIP) • Weights & Measures (Packaged Goods) Regulations 2006 • Plugs and Socket (Safety) Regulations 1994 • The Waste Electronic and Electrical Equipment Regulations 2006 (WEEE) • The Batteries and Accumulators (Placing on the Market) Regulations 2008 • The Waste Batteries and Accumulators Regulations 2009 • Consumer Protection (Distance Selling) Regulations 2000 • Electronic Commerce (EC Directive) Regulations 2002 • Control of Misleading Advertising Regulations (1998) These regulations provide a comprehensive framework for ensuring that electronic cigarette products are indeed safe. What is needed is not more regulation, or a new regulatory framework, but there is a pressing need for better enforcement of these existing regulations. ECITA strives to ensure that its members not only meet, but exceed the legal requirements. Unfortunately, some – although by no means all – non-ECITA members do indeed need more stringent checks from government regulators. Although Trading Standards Officers across the UK are doing their best, the government is simply not giving them the support they need. You report that “[t]o investigate, researchers from the University of Athens examined the effects on eight people who had never smoked.” It seems likely that peer reviewers (and possibly ethics committees) may want answers to the question of why a product, containing nicotine which is known to be addictive, was tested on people who had never smoked, as part of this study? It is fortunate that, despite Professor Gratziou’s claims, the electronic cigarette does not cause proven harm – otherwise these subjects would have a very strong case for legal recourse. You quote Professor Gratziou as saying: “This research helps us to understand how these products could be potentially harmful.” At least she admits that this was the intention of the research, but did she admit the potential for harm she anticipated finding to the people who had never smoked, but whom she invited to participate in her research? In reporting the methodology of this research, you state: “Each person used an electronic cigarette for 10 minutes. The researchers then measured their airway resistance using a number of tests.” You then continue to quote Professor Gratziou as saying: “We do not yet know
whether unapproved nicotine delivery products, such as e-cigarettes, are safer than
normal cigarettes”.
Certainly, her study abstract provides little hope that this research will have added
anything useful to the body of academic knowledge on this subject. Far worse,
however, and most unfortunately, Professor Gratziou’s comment is either a lie, or
indicates an unacceptable level of ignorance from someone speaking as an expert in
these matters. There is no mechanism by which an electronic cigarette can be as
harmful as smoking. Indeed, electronic cigarettes are demonstrably less harmful,
since all the carcinogenic by-products of combustion are eliminated when switching
from smoking to using an electronic cigarette.
Indeed, Professor Michael Siegel’s analysis of Professor Gratziou’s research states:
“The claim is ridiculous, damaging, and ignores all of the existing evidence. While
electronic cigarettes have been shown to cause mild increases in airway resistance
with uncertain clinical implications, we know that cigarette smoking causes chronic
obstructive lung disease. So even if you look only at respiratory effects, there is
strong evidence that smoking is more dangerous than vaping. Moreover, many vapers
have experienced dramatic improvement in respiratory symptoms, which is not
consistent with the argument that smoking may be no more hazardous than vaping in
terms of respiratory effects.”v

All of the chemicals found in electronic cigarettes, with the possible exception of some
of the flavourings (after all, it is impossible to find an absinthe-flavoured tobacco
cigarette), are also found in tobacco cigarettes. The electronic cigarettes, however, do
not deliver carbon monoxide, nitrous oxides or tar, or any of the thousands of other
harmful chemicals found in tobacco smoke. They are also approximately 1,000 times
lower in tobacco’s cancer-causing chemicals, TSNAs, having similar levels to
‘approved’ NRT products. For Professor Gratziou to “not yet know” this basic
information would mean that she is completely unaware of both the constituents of
electronic cigarettes and of tobacco cigarettes. If that is the case, she is not qualified
to express an opinion; if she understands the subject at all, then this can only be a
lie.
Many millions of people around the world enjoy the benefits of caffeine, and nicotine
has many similar benefits. The significant problem about enjoying nicotine has always
been the delivery method: smoking kills. We know this. Electronic cigarettes offer as
‘clean’ a way of taking nicotine as the cup of coffee delivering caffeine. Both products
are regulated by a comprehensive range of laws to ensure that they are indeed of
sufficiently high quality and safe when used as intended.
If this research actually makes it to publication, it will be very interesting to see who sponsored it. Electronic cigarettes are a direct threat to the profits of the pharmaceutical companies which produce ineffective – and sometimes dangerous – NRT and smoking cessation products. Is it hypocrisy, or mere ignorance for Professor Gratziou to support Chantix, and then to suggest there are health problems with electronic cigarettes – despite the fact that her own research appears to agree with other studies, showing that no such problems exist? Or is there something more sinister going on, in attempting to protect the profits of ‘Big Pharma’ when they are threatened by an innovative product which is more effective, more appealing, and over which the pharmaceutical industry can have no control? Perhaps this kind of study has more to do with protecting the funding stream for other study protocols, by declaring the pharmaceutical product ‘effective’ (despite the known hazards) and attempting to create unwarranted fears about the ‘competitor’ product (despite a growing body of evidence to the contrary). Others have suggested there may be a significant conflict of interest: “the media has misrepresented the study findings, due in part to misrepresentation of the study findings by the authors themselves. Even worse, the press release disseminates a completely unsupported conclusion that runs contrary to all existing scientific evidence and which - if made by a tobacco company - would be considered fraudulent. Finally, all of this misrepresentation and deception occurs in the existence of a severe financial conflict of interest which was hidden from the media and the public.”vi Your article goes on to quote Professor Gratziou’s suggesting “[m]ore research is needed to understand whether this harm also has lasting effects in the long-term.” Unfortunately, this is also misleading and inaccurately states that there is (at least) a short-term ‘harm’. Crucially, they failed to compare electronic cigarette use with smoking by measuring airway resistance after smoking, instead observing the effects in comparison with fresh air. This attempt to observe an effect without an appropriate (or meaningful) comparison is not so much comparing apples with oranges as apples with fruit machines. What is desperately needed is more research directly comparing the effects on the body of ecigarette use versus the effects on the body of smoking. Professor Siegel commented on this with reference to another recent study, published by Constantine Vardavas et al, ‘Short-term Pulmonary Effects of Using an Electronic Cigarette: Impact on Respiratory Flow Resistance, Impedance, and Exhaled Nitric Oxide’vii: “… the study failed to compare the acute respiratory effects of electronic cigarette exposure with those of active smoking, which is the most important comparison that needs to be made. “In contrast to what some are reporting, the study found no effect of e-cigarettes on lung function, as measured by spirometry. This is in contrast to tobacco smoking, which does have effects on lung function that can be measured using spirometric testing.”viii “ACSH's Dr. Josh Bloom agrees. ‘The moment I saw that they didn’t run the same experiment using actual cigarettes,’ he says, ‘I knew this was pure (and not even especially well done) junk — an agenda-based report clumsily masquerading as science.’ ix Professor Gratziou is quoted as saying: “The ERS recommends following effective smoking cessation treatment guidelines based on clinical evidence which do not advocate the use of such products.” What, precisely, is Professor Gratziou’s agenda, which leads her to attempt to discredit a product which is demonstrably far safer and healthier for smokers than continuing to smoke tobacco? What can she be trying to protect, since she clearly isn’t interested in what’s best for smokers? Perhaps some of the answers can be found in her previous work. Christina Gratziou was the lead (and correspondence) author on a study of the effectiveness of varenicline (marketed in the US as ‘Chantix’ and in the UK as ‘Champix’) as a quitting aid, published 2nd February 2012. That study was funded by Pfizer, the makers of Chantix. In a Public Health Advisory, the FDA required new warnings for Chantix in July 2009, since it was found to have caused thousands of incidences of suicide, suicidal ideation, violent episodes, and other devastating side effects; yet Professor Gratziou’s study concludes that “varenicline is an effective smoking cessation medication”.x By way of illustrating the severity of this, and to demonstrate the previous misinformation published by Professor Gratziou, it is worth looking closer at the FDA’s revised guidelines for this product, especially since this happened over 3 years ago. The FDA introduced a new box warningxi (the ‘black box’) to the product labelling to alert health care professionals to this important new safety information: In addition to the new Boxed Warning, the FDA is also requiring the manufacturers of Chantix, Zyban, and generic versions of Zyban to describe these risks in the Medication Guides for these products, as follows: “People who are taking Chantix or Zyban and experience any serious and unusual changes in mood or behaviour or who feel like hurting themselves or someone else should stop taking the medicine and call their healthcare professional right away. Friends or family members who notice these changes in behaviour in someone who is taking Chantix or Zyban for smoking cessation should tell the person their concerns and recommend that he or she stop taking the drug and call a healthcare professional right away.”
The so-called “effective smoking cessation treatment[s]” Professor Gratziou and the
ERS recommends, have been shown in more recent studies to be ineffective and in
some cases (such as Chantix), actively dangerous. Public health experts should be
fully aware of recently published studies, such as this one from the Harvard School of
Public Health: ‘Nicotine replacement therapies may not be effective in helping people
quit smoking.’xii

The FDA made a further announcement concerning Chantix just last year:
“Safety Announcement
[6-16-2011] The U.S. Food and Drug Administration (FDA) is notifying the public
that the smoking cessation aid Chantix (varenicline) may be associated with a small,
increased risk of certain cardiovascular adverse events in patients who have
cardiovascular disease.”xiii
I realise that contentious stories sell newspapers, but shouldn’t there be an attempt
to report facts, rather than hearsay? One potentially contentious story we have yet to
see reported is the NHS’s recent figures on quit rates, demonstrating that 4-week
success rates with NRT at around 50% are no better than those without any
pharmacological intervention, also at around 50%, suggesting that the NHS is wasting
millions of pounds on drugs that don’t work.xiv (4 weeks represents the highest point
for quitting, as many relapse after this point. After 1 year, for example, successful
quit rates drop to a paltry 5%, or thereabouts.) Perhaps we can look forward to seeing you report on this soon? Professor Michael Siegel of Boston University School of Public Health describes advice to use approved smoking cessation methods, and disregard harm reduction alternatives, as ‘irresponsible’: “I find this to be irresponsible advice, because these methods that are ‘known to work’ actually are quite ineffective, with dismal results in terms of long-term cessation. Advising smokers to stick with the FDA-approved medications is tantamount to advising the overwhelming majority of smokers to continue smoking.”xv Other public health experts agree with Professor Siegel. Dr Gilbert Ross, Medical Director of the American Council on Science and Health (ACSH) said: “Cessation rates, from utilizing any or all of the standard therapies with medical counseling and follow-up, vary from 5% to 25% at one year. “Telling people ‘quit or die’ doesn't seem to be inspiring much quitting. The ‘harm reduction’ alternatives are the unacknowledged stepchildren of the anti-tobacco movement. These include (a) smokeless tobacco, inspired by the impressive quit rates in Sweden, and (b) the potential delivery of ‘clean nicotine’ via the e-cigarette. But any possible remedy that uses tobacco to help smokers quit … is anathema to anti-tobacco zealots. They ignore the plight of smokers who have tried over and over again to quit and keep relapsing.”xvi Dr Farsalinos, a Fellow at the Onassis Cardiac Surgery Centre, said: “considering the extreme hazards associated with cigarette smoking, currently available data suggest that electronic cigarettes are far less harmful and substituting tobacco with electronic cigarettes may be beneficial to health.”xvii Dr Elizabeth Whelan, President of ACSH commented: “The truth is, the ‘approved’ methods of smoking cessation have a dismal track record, with success rates less than 15 percent after one year. … We desperately need better options.”xviii An ACSH newsletter reported: “This study’s lead researcher recommends that, instead of trying e-cigarettes as a reduced-risk method to quit smoking, smokers should ‘stick to the methods that are known to work.’ But Dr. Ross criticizes this recommendation. ‘He would have more accurately said, “stick to the methods that are known to not work,” since those currently approved have a ‘success’ rate of only 5 to 10 percent. It’s the old ‘quit or die,’ abstinence-only agenda.”xix As these experts have recognised, electronic cigarettes are not in fact intended as a quit smoking product. The reason for the success of the electronic cigarette is that it provides a reduced harm alternative to smoking traditional cigarettes, for those unable or unwilling to forgo nicotine. This is one reason that many in the anti-tobacco
movement dislike electronic cigarettes – they view anything that continues to deliver
nicotine (with the exception of the products made by their ‘friends’ in the
pharmaceutical industry) as being just as bad as smoking, despite the demonstrated
reduction in risk.
One tobacco harm reduction expert, Dr Carl Phillips, put this regrettable and
dangerous tendency to deter smokers from switching to low risk nicotine delivery
methods, in favour of smoking cessation medicines, in fairly stark terms:
“for the average smoker, smoking for just one more month before quitting causes
greater health risk than switching to a low-risk nicotine source and never quitting it.
Thus, discouraging a smoker, even one who would have quit entirely, from switching
to a low-risk alternative is almost certainly more likely to kill him than it is to save
him.”xx
Do both the Mail Online and Professor Gratziou really want to send out the message
that these 650,000 former smokers, who have switched to using electronic cigarettes
– with the demonstrable reduction in risk to themselves and those around them –
should immediately abandon their electronic cigarettes and return to smoking tobacco
cigarettes? Tragically, this is precisely the message your article is delivering.
You report that: “Ministers are concerned… may contain very high levels of nicotine”.
Unless ministers have forgotten their O-Level or GCSE mathematics, it is hard to see
where this concern originates. Where a cartridge is labelled ‘18mg/ml’, this equates to
a mere 1.8% solution. Some cartridges are labelled ‘high’, but the regulations require
clear labelling of the amount of nicotine in the solution. The levels of nicotine in
electronic cigarette products are comparable to those in the ‘approved’ and
‘regulated’ medicinal nicotine inhalator. For more information, please see the ECITA
Quarterly Update.xxi

You state that nicotine is “the addictive substance in cigarettes that has also been
linked to cancer.” There does not seem to be a great deal of evidence to support this,
with both the FDA, (who stated: “The reviewed studies do not indicate severe
pathological alterations after inhalation of nicotine”xxii), and the UK Government, (who
consider nicotine to be “a very safe drug”), approving other products for inhaling
nicotine, such as the Nicotrol inhaler and the Nicorette inhalator. If nicotine has
significant risks associated with it, why are you and others not warning of the risks of
these widely-available NRT products? The link between nicotine and cancer is
primarily a legacy of the delivery of nicotine through tobacco smoking.
Dr Whelan confirms this: “Again, it’s not the nicotine that’s so dangerous about
regular cigarettes, but the toxins and carcinogens in the ‘products of combustion’ —
the smoke — that’s inhaled deep into the lungs and then into the general circulation.
There’s no reason to think e-cigarettes present the same risks, since there’s no
combustion.”xxiii
Whilst Deborah Arnott of ASH seems to have a far better understanding of the science than Professor Gratziou, Ms Arnott is obviously not fully au fait with the extent to which the safety and quality of electronic cigarette products are required to be rigorously tested, under the existing consumer product safety legislation. Your article states: “The Government’s drug’s [sic] watchdog, the Medicine and Healthcare Products Regulatory Agency, will make a decision next spring on whether to introduce stricter checks.” The MHRA is not authorised to “introduce stricter checks”, since electronic cigarettes do not fit the legal definition of a medicinal product. The MHRA’s remit extends only to the regulation of medicines and healthcare products. They cannot randomly decide to regulate consumer products as medicines, in the absence of medicinal claims. The law protects both businesses selling consumer products, as well as the consumers, from aggressive attempts at over-regulation, particularly where there is a better regulatory framework in other legislation. As we have demonstrated, this is clearly the case for electronic cigarettes, and indeed, this has been tested in court on three occasions within the EU, and on each occasion, the attempts to classify electronic cigarette products as medicinal products have been rejected by the courts.xxiv We hope to work with other departments of Government to restrain this “watchdog”, so that the UK government is not dragged into unnecessary – and costly – legal battles it cannot hope to win. It amazes me that journalists are credulous enough to be taken in by the ‘science by press release’ used by some authors to promote the agenda they support. There is a tendency for researchers to ‘spin’ a few quick lines which, when the research is actually published, are not actually supported by the evidence they gathered. Rather than instantly reporting a ‘soundbite’, it would be better to wait until the research is published, and commented on by the author’s peers, so that an accurate report of the contents and context can be made, rather than a presentation of so-called facts that is so distorted, it bears little resemblance to any kind of truth. We are not alone in our concerns that this method of disseminating information does not provide an accurate summary of the actual study results. Professor Michael Siegel has today published his own response to this nonsense: “That this study was released using the "science by press release" method is also problematic. As I have argued before, scientific results should not be released to the media and the public unless either: (1) the study has been peer-reviewed and published; or (2) the entire study is made available publicly so that the work can be properly evaluated. In this case, there is no actual study I am aware of, merely an abstract. Thus, we have no way of evaluating the validity of the findings.”xxv Surely, it behoves all good journalists to do a little research before printing articles. I trust we can expect to see a more accurate – and representative – follow-up article from your publication, at your earliest convenience. Yours sincerely, Katherine Devlin President ECITA (EU) Ltd www.ecita.org.uk i http://www.dailymail.co.uk/news/article-2197430/Electronic-cigarettes-damage-lungs-cause-oxygen-absorbed-blood.html?ito=feeds-newsxml ii https://www.ersnetsecure.org/public/prg_congres.abstract?ww_i_presentation=59718 iii http://tobaccoanalysis.blogspot.com/2012/09/experts-from-university-of-athens-tell.html iv https://www.ersnetsecure.org/public/prg_congres.abstract?ww_i_presentation=59718 v http://tobaccoanalysis.blogspot.com/2012/09/experts-from-university-of-athens-tell.html vi http://tobaccoanalysis.blogspot.com/2012/09/experts-from-university-of-athens-tell.html vii http://journal.publications.chestnet.org/article.aspx?articleid=1187047# viii http://tobaccoanalysis.blogspot.co.uk/2012/01/new-study-shows-that-in-contrast-to.html ix http://www.acsh.org/factsfears/newsID.3305/news_detail.asp x http://www.tobaccoinduceddiseases.com/content/10/1/1/ xi http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/021928s028lbl.pdf xii http://www.eurekalert.org/pub_releases/2012-01/hsop-nrt010512.php xiii http://www.fda.gov/Drugs/Drugsafety/ucm259161.htm xiv http://www.ic.nhs.uk/webfiles/publications/003_Health_Lifestyles/NHS%20Stop%20Smoking%20Services%202011-12/stats_stop_smok_eng_2011_12_rep.pdf xv http://tobaccoanalysis.blogspot.co.uk/2012/01/new-study-shows-that-in-contrast-to.html xvi http://www.acsh.org/factsfears/newsID.1242/news_detail.asp xvii http://www.noodls.com/viewNoodl/15626744/esc---european-society-of-cardiology/electronic-cigarettes-do-not-damage-the-heart xviii http://www.acsh.org/healthissues/newsID.1913/healthissue_detail.asp xix http://www.acsh.org/factsfears/newsID.3305/news_detail.asp xx http://www.harmreductionjournal.com/content/pdf/1477-7517-6-29.pdf xxi http://www.ecita.org.uk/ecita%20quarterly%20update.pdf xxii http://www.accessdata.fda.gov/drugsatfda_docs/nda/97/20714_NICOTROL%20INHALER%2010MG,%20CARTRIDE_PHARMR.PDF xxiii http://www.acsh.org/healthissues/newsID.1913/healthissue_detail.asp xxiv United Tobacco Vapor Group Inc. versus the State of the Netherlands (the Ministry of Health, Welfare and Sport and the Ministry of Finance), in the Netherlands Court of the Hague, [2012], Case number 414117 Rechtspraak.nl - LJN: BV8613. na.presseportal, E-Zigarette SNOKE® ist Genussmittel, kein Arzneimittel/ecoreal GmbH & CO KG feiert Erfolg vor dem Oberverwaltungsgericht, 26th March 2012 E-Zigarette SNOKE® ist Genussmittel, kein Arzneimittel | ecoreal GmbH & Co. KG | Presseportal.de Wahrheit über ezigaretten.de, Court ruling from Saxony-Anhalt, Case no. 3M129/12, 5th June 2012 http://www.wahrheit-ueber-ezigaretten.de/images/pdf/stories/pdf/OVG-LSA-20120605.pdf xxv http://tobaccoanalysis.blogspot.com/2012/09/experts-from-university-of-athens-tell.html

Source: http://www.ecita.org.uk/docs/Letter_to_Mail_Online_%20060912.pdf